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DKK3 expression and function in head and neck squamous cell carcinoma and other cancers
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Contents lists available at ScienceDirect
Journal of Oral Biosciences journal homepage: www.elsevier.com/locate/job
Review
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DKK3 expression and function in head and neck squamous cell carcinoma and other cancers
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Naoki Katase *, Kenichi Nagano , Shuichi Fujita Department of Oral Pathology, Institute of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki, Nagasaki, 852-8588, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 13 December 2019 Received in revised form 24 January 2020 Accepted 27 January 2020 Available online xxx
Background: Cancer arises from cumulative genetic or epigenetic aberrations, or the destabilization of central signaling pathways that regulate cell proliferation, differentiation, cell cycle, gene transcription, migration, angiogenesis and apoptosis. Investigating the cancer-specific genetic background is important to get deeper apprehension of cancer biology. In this review, we aimed to identify head and neck squamous cell carcinoma (HNSCC)-specific genes and identified DKK3 gene as a candidate. Highlight: DKK3 belongs to the DKK family (DKK1, DKK2, DKK3 and DKK4), which codes for an evolutionally conserved secreted glycoprotein that is characterized by two distinct cysteine rich domains and functions as an antagonist of the oncogenic Wnt signaling pathway. It has been reported that DKK3 expression is decreased in many kinds of cancers, and it is thus thought to be a tumor suppressor gene. However, our investigations have demonstrated unique expression and function of DKK3 in HNSCC. DKK3 protein expression is predominantly positive in HNSCC, and DKK3-positive patients show significantly shorter disease-free survival rates, whereas DKK3-negative cases do not show metastasis. Molecular biological analyses demonstrated that DKK3 over expression significantly increased HNSCC cell proliferation, migration, and invasion via increased phosphorylation of AKT. Moreover, DKK3 knockdown in HNSCC cells significantly decreased these malignant potentials through decreased AKT phosphorylation. Conclusion: Our previously published data, alongside those from other reports, indicate that DKK3 may have an additional oncogenic function other than tumor suppression. © 2020 Published by Elsevier B.V. on behalf of Japanese Association for Oral Biology.
Keywords: DKK3 Head and neck squamous cell carcinoma Oncogene Tumor suppressor gene
Contents 1. 2. 3. 4. 5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The function of DKK3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tumor suppresser function of DKK3 in cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Oncogenic functions of DKK3 in HNSCC and other cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ethical approval . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CRediT authorship contribution statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abbreviations: DKK3, dickkopf WNT signaling pathway inhibitor family 3. * Corresponding author. E-mail address: [email protected] (N. Katase). https://doi.org/10.1016/j.job.2020.01.008 1349-0079/© 2020 Published by Elsevier B.V. on behalf of Japanese Association for Oral Biology.
Please cite this article as: Katase N et al., DKK3 expression and function in head and neck squamous cell carcinoma and other cancers, Journal of Oral Biosciences, https://doi.org/10.1016/j.job.2020.01.008
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1. Introduction Generally, it is believed that cancers arise as a result of cumulative genetic/epigenetic abnormalities in cells, which effectuate serious impairments of important cellular process and signaling pathways. Recent developments made through next generation sequencing have highlighted that every cancer has a tumor- and organ-specific gene expression profile. The cancer-specific gene expression profiles differ by histological type of the cancer and/or its originating organ. Moreover, some of the known gene aberrations are often shared by different cancer types. For instance, mutations of TP53, PIK3CA, KRAS, PTEN, ARID1A are commonly observed in many cancer types, and mutations in ZNF750, KLF5, KMT2D, PIK3CA, PTEN and MAPK1 have been detected in all squamous cancer types [1]. To date, the cancer genome atlas (TCGA) publications have focused on the signaling pathway that are likely to be drivers of the development and progression of cancers, including cell cycle, Hippo signaling, Myc signaling, Notch signaling, PI3K signaling, p53, Receptor tyrosine kinase (RTK) signaling, TGF-b signaling, and Wnt/b-catenin signaling [2]. However, the key genes or pathways that may function as cancer drivers for head and neck squamous cell carcinoma (HNSCC) are yet to be investigated. In this context, we have been seeking HNSCCspecific cancer-associated genes, and through this work, we detected the DKK3 gene as a cancer driver candidate gene. At first, we found DKK3 to act as a candidate tumor suppressor detected at the highly frequently deleted chromosomal loci in HNSCC, by genome wide loss of heterozygosity (LOH) analysis [3,4]. However, a series of our studies have shown an HNSCC-specific oncogenic function of DKK3 [5e9]. Thus, in this article, we review the expression and function of DKK3 in cancers. 2. The function of DKK3 DKK3, formerly named dickkopf 3 homolog (Xenopus laevis) [10], belongs to the Dickkopf WNT signaling pathway inhibitor family. The DKK family members DKK1, DKK2, DKK3 and DKK4 encode secretory proteins with two distinct cysteine rich domains, which function as endogenous Wnt signaling inhibitors. Wnt signal is an evolutionarily conserved signaling pathway that plays important roles in morphogenesis and carcinogenesis, and therefore is regulated both positively and negatively by numerous effector molecules. Secreted Wnt ligands act as multilateral factors that activate three distinct intracellular signal cascades, the Wnt/b-catenin signaling pathway, Wnt/Planar cell polarity pathway (PCP), and the Wnt/Ca2þ pathway. Amongst these signaling pathways, Wnt/b-catenin signaling pathway (also known as the canonical pathway) is the most well-known signaling cascade [11,12]. This pathway is stimulated when the Wnt ligands bind to its receptor complex, Frizzled (FZD) and Low-density lipoprotein receptor-related receptor, (LRP) 5/6. This binding causes the stabilization of cytoplasmic CΤNNВ1 and consequently, its nuclear translocation. Translocated CΤNNВ1 acts as an activator of the transcription factor T-cell factor/lymphoid enhancer binding factor (TCF/LEF) and increases the transcription of target genes, including MYC, CCND1, and JUN [11,13]. This oncogenic signal is regulated by secreted Wnt inhibitors, secreted Frizzled-related proteins (SFRPs), Wnt inhibitory factor 1 (WIF1), and DKK family members. The former two secreted proteins directly bind to Wnt ligands in the extracellular environment, thereby sequestering the Wnt ligand from the Wnt receptors [14,15]. At variance with these proteins, DKK1, DKK2 and DKK4 inhibit Wnt signaling by binding to the receptor KREMEN1, and induce internalization of LRP5/6 by endocytosis. As a result, this shuts down the Wnt signal [16,17]. Furthermore, DKK3 lacks the ability to bind to either LRP5/6 or
KREMEN1 due to the presence of 7 amino acids in its second cysteine rich domain [18]. Thus, it has been proposed that DKK3 does not possess Wnt/b-catenin inhibitory function. However, Leonard JL et al. has reported that the DKK3 gene also codes for a cytoplasmic, non-secreted isoform, DKK3b, which shuts off Wnt/bcatenin signaling by binding to BTRC ubiquitin ligase. This causes inhibition of CΤNNВ1 nuclear translocation [19] (Fig. 1). For this reason, all DKK family members act as Wnt/b-catenin signaling inhibitors, which function via interaction with receptors on the cell surface or with cytoplasmic partner proteins. The Wnt/b-catenin signaling pathway is often deregulated in a variety of human cancers and diseases. In cancer, especially in the adenocarcinomas of the gastrointestinal tract, up-regulation of Wnt/b-catenin signaling genes and down-regulation of Wnt inhibitory genes by hypermethylation of CpG islands are very common events that occur in the pathogenic process of the disease [20]. DKK3 also has CpG islands and is susceptive to methylation, however, the start codon for DKK3b is distantly positioned from the CpG island (Fig. 2). This means that DKK3 may behave as the “last defense” against the down-regulation of Wnt signaling inhibitors, even under conditions where all other family members have been methylated. 3. Tumor suppresser function of DKK3 in cancers In addition to having a Wnt inhibitory function, DKK3 is also characterized as a tumor suppressor as its expression is reduced in many kinds of malignancies; thus, it is firstly named as “Reduced Expression in Immortalized Cells” (REIC) gene. Tsuji and colleagues discovered the gene by searching immortalization-related genes in immortalized cells, and cloning of the cDNA and predicted amino acid sequence reveled that REIC is identical to human DKK3 [11,21]. To date, DKK3 mRNA and protein expression is found to be downregulated in many types of solid tumors and hematopoietic malignancies [8,10,11,13] in the following order: non-small cell lung cancer (NSCLC) [22], renal cell carcinoma [23], osteosarcoma [24], prostatic carcinoma [25], pancreatic adenocarcinoma [26], bladder carcinoma [27], malignant melanoma [28], gastric and colorectal adenocarcinoma [20,29], glioma [30], testicular carcinoma [31], breast cancers [32], hepatocellular carcinoma [33], cervical Squamous cell carcinoma (SCC) [34], esophageal SCC [35], ovarian cancer [36], cutaneous SCC [37] and leukemias [38e40]. All of these reports indicated reduced mRNA and protein expression of DKK3 in cancers, and it has been confirmed that the reduced expression of DKK3 is caused by hypermethylation of the CpG island in the DKK3 promoter region [41]. This hypermethylation is a tumor-specific event which is not observed in the adjacent normal tissue [11,32,41], and demethylation treatment can restore DKK3 expression and function in several cancer cells [32,40,41]. Further, these reports strongly suggest the tumor suppressor function of DKK3, which has been supported by in vivo and in vitro evidence indicating that inhibition of tumor cell proliferation, invasion, migration, anchorage-independent growth and apoptosis by DKK3. It has also been reported that DKK3 over-expression in cancer cells resulted in interference of Wnt/b-catenin signaling and consequent reduction of cell proliferation or invasion in colorectal cancer [42], pancreatic cancer [26], cervical SCC [34], endometrial cancer [43] and renal cell carcinoma [44]. DKK3 over-expression also activates c-Jun N-terminal kinase (JNK) and induces apoptosis in glioma [30], bladder cancer [45], prostate cancer [25], testicular cancer [31], and NSCLC [46]. Based on these convincing studies, DKK3 is considered to be a potential therapeutic target. The most promising approach for DKK3-targeted cancer therapy is intra-tumoral injection of an
Please cite this article as: Katase N et al., DKK3 expression and function in head and neck squamous cell carcinoma and other cancers, Journal of Oral Biosciences, https://doi.org/10.1016/j.job.2020.01.008
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Fig. 1. The Wnt/b-catenin signaling pathway and its inhibition by DKK family. The binding of Wnt ligand to its receptor, Frizzled and LRP5/6 leads to the stabilization of b-catenin and, consequently, the transcription of its target genes. DKK family members (DKK1, 2, and 4) bind to LRP5/6 and Kremen, and inhibit Wnt/b-catenin signaling by sequestration of Wnt receptors. DKK3 does not bind to LRP5/6; instead, its cytoplasmic isoform, DKK3b, inhibits the nuclear translocation of b-catenin.
adenovirus vector carrying REIC/DKK3 gene (Ad-REIC), with an aim to initiate re-expression of the DKK3 gene in DKK3 defeated malignant tissues. It was reported that adenovirus-mediated fulllength DKK3 cDNA expression successfully exerts anti-cancer effects in the subcutaneous xenograft models of prostatic [25], testicular [31], and breast cancers [47] and orthotopic cancer models of prostate cancer [48], malignant mesothelioma [47], and scirrhous gastric carcinoma [49]. Moreover, ad-REIC significantly suppressed cancer cell proliferation and increased apoptosis, it has also been suggested that ad-REIC may also activate anticancer immunity [50]. Now, ad-REIC research is addressing its clinical application for cancer treatment. A Phase I/IIa in situ Ad-REIC gene therapy trial for prostate cancer is ongoing (UMIN000004929; NCT01931046). In addition, direct and systemic anticancer effects have been detected in a patient with metastatic castration-resistant prostate cancer [51]. However, there are some controversial reports for ad-REIC treatment. Some reports have suggested that over-expression of DKK3 may not cause apoptosis or affect cellular proliferation of cancer cells, either by transient overexpression or stable overexpression of DKK3 [8,31,52e55]. Zenzmaier and colleagues have hypothesized that reported anti-proliferative or pro-apoptotic effects of DKK3 over-expression, as a result of the unfolded protein response, are in vitro artifacts that do not reflect the biological role of the endogenous DKK3 protein [55]. Although DKK3 may be a promising anticancer target, further investigation is needed to examine the possibility of Ad-REIC gene therapy.
4. Oncogenic functions of DKK3 in HNSCC and other cancers As mentioned above, DKK3 shows obvious tumor suppressive functions in several cancers. Nevertheless, DKK3 function in HNSCC is completely different and indicates complex oncogenic function. We first identified the DKK3 gene as a HNSCC-specific tumorassociated gene by LOH analysis [3]. LOH analysis is a sensitive method to detect microdeletions in specific regions on the
chromosome and is critical for the identification of tumor suppressor genes (TSG) [4]. We found that chromosomal loci, including DKK3 (11p15.2), are frequently deleted in HNSCC cancer tissue; thus, we initially identified DKK3 as a TSG. However, a DKK3-LOH (þ) status is correlated with less lymph node metastasis and favorable overall survival [3]. Therefore, we next investigated the protein expression of DKK3 by immunohistochemistry in HNSCC and precursor lesions. The results showed that DKK3 expression was low and membranous in normal tissue, however, it increased in epithelial dysplasia and cancers with cytoplasmic expression [5]. Interestingly, DKK3 protein expression was observed in more than 84% of the 90 cases of HNSCC tissue samples, and survival analysis showed that the DKK3 () patients exhibited significantly longer disease-free survival rates, metastasis-free survival rates, and longer overall survival rates [6]. These results led us to hypothesize that DKK3 may possess oncogenic function specifically in HNSCC, and we thus investigated the effects of transient knockdown of DKK3 by siRNA in HNSCC cells. Supporting our hypothesis, the siRNA transfection did not affect cell proliferation, however, it significantly decreased cell migration and invasion by signaling pathways other than Wnt/bcatenin signaling [7]. To investigate the detailed mechanism by which DKK3 exerts oncogenic function in HNSCC, we established an over-expression model by transfection of a full-length DKK3 expressing plasmid and a stable knockdown model by infection of a lentivirus carrying specific shRNA targeting DKK3. The over-expression of DKK3 resulted in significantly elevated cellular proliferation, migration, invasion and in vivo tumor growth, together with significantly increased Wnt target genes including MYC and CCND1. However, the TCF/LEF activity was not changed by DKK3 transfection, implying that these elevated malignant potentials by DKK3 may not be caused by Wnt/b-catenin signaling. Microarray and western blotting analyses revealed that DKK3 augmented the malignancy of HNSCC cells by increasing the phosphorylation of AKT [8]. Moreover, the stable knockdown of DKK3 significantly decreased cellular proliferation, migration, invasion and in vivo
Please cite this article as: Katase N et al., DKK3 expression and function in head and neck squamous cell carcinoma and other cancers, Journal of Oral Biosciences, https://doi.org/10.1016/j.job.2020.01.008
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Fig. 2. Gene sequence of DKK3 and the corresponding protein sequence. The start codons are indicated in red. The start codon with an asterisk (*) indicates the start codon for DKK3b. The signal peptide is indicated in blue, and cysteine rich domains (Cys-1 and Cys-2) are indicated by green and yellow lines, respectively. The predicted coiled-coil structure is underlined.
Please cite this article as: Katase N et al., DKK3 expression and function in head and neck squamous cell carcinoma and other cancers, Journal of Oral Biosciences, https://doi.org/10.1016/j.job.2020.01.008
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66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 Fig. 3. Prospective role of DKK3 in HNSCC. All of our data suggest that DKK3 may bind to some receptors and activate Akt via PI3K/PDK1 and via the activation of the mTOR complex 89 by the DKK3b/bTrCP-mediated degradation of DEPTOR. 90 91 92 mechanisms underlying DKK3 function in different tumor cell tumor growth. The combination of microarray analysis, pathway 93 environments. analysis and western blotting analysis demonstrated that levels of 94 phosphorylated AKT, PI3K, PDK1 and total p38 MAPK were reduced. 95 Furthermore, phosphorylation of mTOR was slightly decreased in 96 5. Conclusions HSC-3 shDKK3 cells, which may be due to the increased expression 97 of DEPTOR. Conversely, DKK3 over-expression in DKK3 knockdown 98 DKK3 is a very interesting molecule that may behave as an cells improved cellular proliferation, migration, and invasion with 99 oncogene or tumor suppressor gene, depending on the cellular elevation of phosphorylated AKT and p38 MAPK signaling [9]. 100 context and cancer type. In either case, there is a plethora of inBased on the results, we predicted that DKK3 may modulate cancer 101 formation now available that highlights how DKK3 is an obvious cell malignant potentials by activating AKT thorough the binding of 102 candidate therapeutic target for cancer therapy. DKK3 to receptors and by intracellular protein-protein interactions 103 of DKK3b (Fig. 3). 104 Our investigations strongly suggest an oncogenic function of 105 Ethical approval DKK3. Moreover, we investigated the correlation between DKK3 106 expression and patient prognosis in various kinds of malignancies 107 Ethical approval was not required for this review article. using databases provided by TCGA. Notably, high mRNA expression 108 levels of DKK3 were an unfavorable prognostic marker for HNSCC, 109 pancreatic and renal cancers, despite previous reports suggesting 110 Conflicts of interest the tumor suppressive role of DKK3. Conversely, high DKK3 mRNA 111 expression was associated with a favorable prognosis in prostate 112 The authors declare no competing interest. cancer, which is in accordance with a previous finding [9]. 113 This suggests that DKK3 may possess tumor- or tissue-specific 114 roles. Supporting our tentative theory, recent reports also suggest 115 Funding oncogenic roles of DKK3 in cancers. In fact, it is indicated that 116 30e50% of cancers in the liver, endometrium, ovary, lung, and 117 The work was supported by a Grant-in-Aid for Scientific brain are DKK3-positive [36,56,57], and oncogenic effects of DKK3 118 Research (C) from the ministry of Education, Culture, Sports, Scihave been reported even in cancers other than HNSCC [57e59]. In 119 ence and Technology (Japan Society for the Promotion of Science, lung adenocarcinoma, DKK3 positive cases show more progressive 120 KAKENHI Grant no. 16K11470 to NK) and the Takeda Science tumor stages and metastatic statuses, and DKK3-knockdown in Foundation (grant no. 2018047114 to NK). Q2 121 lung adenocarcinoma cells shows less invasive phenotypes [57]. 122 Up-regulation of DKK3 in esophageal squamous cell carcinoma 123 (ESCC) has been reported [60], and very recently, Kajiwara and 124 CRediT authorship contribution statement colleagues have reported that DKK3 is expressed in approximately 125 50% of ESCC tissues, and simultaneous expression of DKK3 and 126 Naoki Katase: Conceptualization, Data curation, Formal analCKAP4 was associated with a poor prognosis [61]. Moreover, 127 ysis, Funding acquisition, Validation, Writing - original draft, stromal expression of DKK3 is reported to be associated with 128 Writing - review & editing. Kenichi Nagano: Validation, Writing aggressive breast, colorectal, and ovarian cancers [62]. Thus, going 129 review & editing. Shuichi Fujita: Validation, Writing - review & forward, it will be important to investigate the molecular 130 editing. Please cite this article as: Katase N et al., DKK3 expression and function in head and neck squamous cell carcinoma and other cancers, Journal of Oral Biosciences, https://doi.org/10.1016/j.job.2020.01.008
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Acknowledgements We thank Dr. Shin-ichiro Nishimatsu (Department of Natural Sciences, Kawasaki Medical School), Dr. Akira Yamauchi (Department of Biochemistry, Kawasaki Medical School) and Dr. Masahiro Yamamura (Department of Clinical oncology, Kawasaki Medical School) for their collaboration in our works. References [1] Bailey MH, Tokheim C, Porta-Pardo E, Sengupta S, Bertrand D, et al. Comprehensive characterization of cancer driver genes and mutations. Cell 2018;173:371e5. [2] Sanchez-Vega F Mina M, Armenia J, Chatila WK, Luna A, et al. Oncogenic signaling pathways in the cancer genome atlas. Cell 2018;173:321e37. [3] Katase N, Gunduz M, Beder LB, Gunduz E, Lefeuvre M, Hatipoglu OF, Borkosky SS, Tamamura R, Tominaga S, Yamanaka N, Shimizu K, Nagai N, Nagatsuka H. Deletion at Dickkopf (Dkk-3) locus (11p15.2) is related with lower lymph node metastasis and better prognosis in head and neck squamous cell carcinoma. Oncol. Res. 2008;17:273e82. [4] Katase N, Gunduz M, Beder LB, Gunduz E, Al Sheikh Ali M, Tamamura R, Yaykasli KO, Yamanaka N, Shimizu K, Nagatsuka H. Frequent allelic loss of dkk-1 locus (10q11.2) is related with low distant metastasis and better prognosis in head and neck squamous cell carcinomas. Canc. Invest. 2010;28: 103e10. [5] Fujii M, Katase N, Lefeuvre M, Gunduz M, Buery RR, Tamamura R, Tsujigiwa H, Nagatsuka H. Dickkopf (Dkk)-3 and b-catenin expressions increased in the transition from normal oral mucosal to oral squamous cell carcinoma. J. Mol. Histol. 2011;42:499e504. [6] Katase N, Lefeuvre M, Gunduz M, Gunduz E, Beder LB, Grenman R, Fujii M, Tamamura R, Tsujigiwa H, Nagatsuka H. Absence of Dickkopf (Dkk)-3 protein expression is correlated with longer disease free survival and lower incidence of metastasis in head and neck squamous cell carcinoma. Oncol Lett 2012;3: 273e80. [7] Katase N, Lefeuvre M, Tsujigiwa H, Fujii M, Ito S, Tamamura R, Buery RR, Gunduz M, Nagatsuka H. Knockdown of Dkk-3 decreases cancer cell migration and invasion independently of the Wnt pathways in oral squamous cell carcinoma-derived cells. Oncol. Rep. 2013;29:1349e55. [8] Katase N, Nishimatsu S, Yamauchi A, Yamamura M, Terada K, Itadani M, Okada N, Hassan NMM, Nagatsuka H, Ikeda T, Nohno T, Fujita S. DKK3 overexpression increases malignant property of head and neck squamous cell carcinoma cells. Oncol. Res. 2018;26:45e58. [9] Katase N, Nishimatsu S, Yamauchi A, Yamamura M, Fujita S. DKK3 knockdown confers negative effects on malignant potency of head and neck squamous cell carcinoma cells via PI3K/Akt signal and MAPK pathways. Int. J. Oncol. 2019;54:1021e32. [10] Katase N, Nohno T. DKK3 (dickkopf 3 homolog (Xenopus laevis)). Atlas Genet Cytogenet Oncol Haematol 2013;17:678e86. [11] Veeck J, Dahl E. Targeting the Wnt pathway in cancer: the emerging role of Dickkopf-3. Biochim. Biophys. Acta 2012;1825:18e28. [12] Klaus A, Birchmeier W. Wnt signalling and its impact on development and cancer. Nat. Rev. Canc. 2008;8:387e98. [13] Niehrs C. Function and biological roles of the Dickkopf family of Wnt modulators. Oncogene 2006;25:7469e81. [14] Tortelote GG, Reis RR, de Almeida Mendes F, Abreu JG. Complexity of the Wnt/ b-catenin pathway: searching for an activation model. Cell. Signal. 2017;40: 30e43. [15] Chien AJ, Conrad WH, Moon RT. A Wnt survival guide: from flies to human disease. J. Invest. Dermatol. 2009;129:1614e27. [16] Mao B, Wu W, Li Y, Hoppe D, Stannek P, Glinka A, Niehrs C. LDL-receptorrelated protein 6 is a receptor for Dickkopf proteins. Nature 2001;411:321e5. [17] Bafico A, Liu G, Yaniv A, Gazit A, Aaronson SA. Novel mechanism of Wnt signalling inhibition mediated by Dickkopf-1 interaction with LRP6/Arrow. Nat. Cell Biol. 2001;3:683e6. [18] Fujii Y, Hoshino T, Kumon H. Molecular simulation analysis of the structure complex of C2 domains of DKK family members and b-propeller domains of LRP5/6: explaining why DKK3 does not bind to LRP5/6. Acta Med. Okayama 2014;68:63e78. [19] Leonard JL, Leonard DM, Wolfe SA, Liu J, Rivera J, Yang M, Leonard RT, Johnson JPS, Kumar P, Liebmann KL, Tutto AA, Mou Z, Simin KJ. The Dkk3 gene encodes a vital intracellular regulator of cell proliferation. PloS One 2017;12: e0181724. [20] Maehata T, Taniguchi H, Yamamoto H, Nosho K, Adachi Y, Miyamoto N, Miyamoto C, Akutsu N, Yamaoka S, Itoh F. Transcriptional silencing of Dickkopf gene family by CpG island hypermethylation in human gastrointestinal cancer. World J. Gastroenterol. 2008;14:2702e14. [21] Tsuji T, Miyazaki M, Sakaguchi M, Inoue Y, Namba M. A REIC gene shows down-regulation in human immortalized cells and human tumor-derived cell lines. Biochem. Biophys. Res. Commun. 2000;268:20e4. [22] Nozaki I, Tsuji T, Iijima O, Ohmura Y, Andou A, Miyazaki M, Shimizu N, Namba M. Reduced expression of REICDKK3 gene in non-small cell lung cancer. Int. J. Oncol. 2001;19:117e21.
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Contents lists available at ScienceDirect
Journal of Oral Biosciences journal homepage: www.elsevier.com/locate/job
Review
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DKK3 expression and function in head and neck squamous cell carcinoma and other cancers
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Naoki Katase *, Kenichi Nagano , Shuichi Fujita Department of Oral Pathology, Institute of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki, Nagasaki, 852-8588, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 13 December 2019 Received in revised form 24 January 2020 Accepted 27 January 2020 Available online xxx
Background: Cancer arises from cumulative genetic or epigenetic aberrations, or the destabilization of central signaling pathways that regulate cell proliferation, differentiation, cell cycle, gene transcription, migration, angiogenesis and apoptosis. Investigating the cancer-specific genetic background is important to get deeper apprehension of cancer biology. In this review, we aimed to identify head and neck squamous cell carcinoma (HNSCC)-specific genes and identified DKK3 gene as a candidate. Highlight: DKK3 belongs to the DKK family (DKK1, DKK2, DKK3 and DKK4), which codes for an evolutionally conserved secreted glycoprotein that is characterized by two distinct cysteine rich domains and functions as an antagonist of the oncogenic Wnt signaling pathway. It has been reported that DKK3 expression is decreased in many kinds of cancers, and it is thus thought to be a tumor suppressor gene. However, our investigations have demonstrated unique expression and function of DKK3 in HNSCC. DKK3 protein expression is predominantly positive in HNSCC, and DKK3-positive patients show significantly shorter disease-free survival rates, whereas DKK3-negative cases do not show metastasis. Molecular biological analyses demonstrated that DKK3 over expression significantly increased HNSCC cell proliferation, migration, and invasion via increased phosphorylation of AKT. Moreover, DKK3 knockdown in HNSCC cells significantly decreased these malignant potentials through decreased AKT phosphorylation. Conclusion: Our previously published data, alongside those from other reports, indicate that DKK3 may have an additional oncogenic function other than tumor suppression. © 2020 Published by Elsevier B.V. on behalf of Japanese Association for Oral Biology.
Keywords: DKK3 Head and neck squamous cell carcinoma Oncogene Tumor suppressor gene
Contents 1. 2. 3. 4. 5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The function of DKK3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tumor suppresser function of DKK3 in cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Oncogenic functions of DKK3 in HNSCC and other cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ethical approval . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CRediT authorship contribution statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abbreviations: DKK3, dickkopf WNT signaling pathway inhibitor family 3. * Corresponding author. E-mail address: [email protected] (N. Katase). https://doi.org/10.1016/j.job.2020.01.008 1349-0079/© 2020 Published by Elsevier B.V. on behalf of Japanese Association for Oral Biology.
Please cite this article as: Katase N et al., DKK3 expression and function in head and neck squamous cell carcinoma and other cancers, Journal of Oral Biosciences, https://doi.org/10.1016/j.job.2020.01.008
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1. Introduction Generally, it is believed that cancers arise as a result of cumulative genetic/epigenetic abnormalities in cells, which effectuate serious impairments of important cellular process and signaling pathways. Recent developments made through next generation sequencing have highlighted that every cancer has a tumor- and organ-specific gene expression profile. The cancer-specific gene expression profiles differ by histological type of the cancer and/or its originating organ. Moreover, some of the known gene aberrations are often shared by different cancer types. For instance, mutations of TP53, PIK3CA, KRAS, PTEN, ARID1A are commonly observed in many cancer types, and mutations in ZNF750, KLF5, KMT2D, PIK3CA, PTEN and MAPK1 have been detected in all squamous cancer types [1]. To date, the cancer genome atlas (TCGA) publications have focused on the signaling pathway that are likely to be drivers of the development and progression of cancers, including cell cycle, Hippo signaling, Myc signaling, Notch signaling, PI3K signaling, p53, Receptor tyrosine kinase (RTK) signaling, TGF-b signaling, and Wnt/b-catenin signaling [2]. However, the key genes or pathways that may function as cancer drivers for head and neck squamous cell carcinoma (HNSCC) are yet to be investigated. In this context, we have been seeking HNSCCspecific cancer-associated genes, and through this work, we detected the DKK3 gene as a cancer driver candidate gene. At first, we found DKK3 to act as a candidate tumor suppressor detected at the highly frequently deleted chromosomal loci in HNSCC, by genome wide loss of heterozygosity (LOH) analysis [3,4]. However, a series of our studies have shown an HNSCC-specific oncogenic function of DKK3 [5e9]. Thus, in this article, we review the expression and function of DKK3 in cancers. 2. The function of DKK3 DKK3, formerly named dickkopf 3 homolog (Xenopus laevis) [10], belongs to the Dickkopf WNT signaling pathway inhibitor family. The DKK family members DKK1, DKK2, DKK3 and DKK4 encode secretory proteins with two distinct cysteine rich domains, which function as endogenous Wnt signaling inhibitors. Wnt signal is an evolutionarily conserved signaling pathway that plays important roles in morphogenesis and carcinogenesis, and therefore is regulated both positively and negatively by numerous effector molecules. Secreted Wnt ligands act as multilateral factors that activate three distinct intracellular signal cascades, the Wnt/b-catenin signaling pathway, Wnt/Planar cell polarity pathway (PCP), and the Wnt/Ca2þ pathway. Amongst these signaling pathways, Wnt/b-catenin signaling pathway (also known as the canonical pathway) is the most well-known signaling cascade [11,12]. This pathway is stimulated when the Wnt ligands bind to its receptor complex, Frizzled (FZD) and Low-density lipoprotein receptor-related receptor, (LRP) 5/6. This binding causes the stabilization of cytoplasmic CΤNNВ1 and consequently, its nuclear translocation. Translocated CΤNNВ1 acts as an activator of the transcription factor T-cell factor/lymphoid enhancer binding factor (TCF/LEF) and increases the transcription of target genes, including MYC, CCND1, and JUN [11,13]. This oncogenic signal is regulated by secreted Wnt inhibitors, secreted Frizzled-related proteins (SFRPs), Wnt inhibitory factor 1 (WIF1), and DKK family members. The former two secreted proteins directly bind to Wnt ligands in the extracellular environment, thereby sequestering the Wnt ligand from the Wnt receptors [14,15]. At variance with these proteins, DKK1, DKK2 and DKK4 inhibit Wnt signaling by binding to the receptor KREMEN1, and induce internalization of LRP5/6 by endocytosis. As a result, this shuts down the Wnt signal [16,17]. Furthermore, DKK3 lacks the ability to bind to either LRP5/6 or
KREMEN1 due to the presence of 7 amino acids in its second cysteine rich domain [18]. Thus, it has been proposed that DKK3 does not possess Wnt/b-catenin inhibitory function. However, Leonard JL et al. has reported that the DKK3 gene also codes for a cytoplasmic, non-secreted isoform, DKK3b, which shuts off Wnt/bcatenin signaling by binding to BTRC ubiquitin ligase. This causes inhibition of CΤNNВ1 nuclear translocation [19] (Fig. 1). For this reason, all DKK family members act as Wnt/b-catenin signaling inhibitors, which function via interaction with receptors on the cell surface or with cytoplasmic partner proteins. The Wnt/b-catenin signaling pathway is often deregulated in a variety of human cancers and diseases. In cancer, especially in the adenocarcinomas of the gastrointestinal tract, up-regulation of Wnt/b-catenin signaling genes and down-regulation of Wnt inhibitory genes by hypermethylation of CpG islands are very common events that occur in the pathogenic process of the disease [20]. DKK3 also has CpG islands and is susceptive to methylation, however, the start codon for DKK3b is distantly positioned from the CpG island (Fig. 2). This means that DKK3 may behave as the “last defense” against the down-regulation of Wnt signaling inhibitors, even under conditions where all other family members have been methylated. 3. Tumor suppresser function of DKK3 in cancers In addition to having a Wnt inhibitory function, DKK3 is also characterized as a tumor suppressor as its expression is reduced in many kinds of malignancies; thus, it is firstly named as “Reduced Expression in Immortalized Cells” (REIC) gene. Tsuji and colleagues discovered the gene by searching immortalization-related genes in immortalized cells, and cloning of the cDNA and predicted amino acid sequence reveled that REIC is identical to human DKK3 [11,21]. To date, DKK3 mRNA and protein expression is found to be downregulated in many types of solid tumors and hematopoietic malignancies [8,10,11,13] in the following order: non-small cell lung cancer (NSCLC) [22], renal cell carcinoma [23], osteosarcoma [24], prostatic carcinoma [25], pancreatic adenocarcinoma [26], bladder carcinoma [27], malignant melanoma [28], gastric and colorectal adenocarcinoma [20,29], glioma [30], testicular carcinoma [31], breast cancers [32], hepatocellular carcinoma [33], cervical Squamous cell carcinoma (SCC) [34], esophageal SCC [35], ovarian cancer [36], cutaneous SCC [37] and leukemias [38e40]. All of these reports indicated reduced mRNA and protein expression of DKK3 in cancers, and it has been confirmed that the reduced expression of DKK3 is caused by hypermethylation of the CpG island in the DKK3 promoter region [41]. This hypermethylation is a tumor-specific event which is not observed in the adjacent normal tissue [11,32,41], and demethylation treatment can restore DKK3 expression and function in several cancer cells [32,40,41]. Further, these reports strongly suggest the tumor suppressor function of DKK3, which has been supported by in vivo and in vitro evidence indicating that inhibition of tumor cell proliferation, invasion, migration, anchorage-independent growth and apoptosis by DKK3. It has also been reported that DKK3 over-expression in cancer cells resulted in interference of Wnt/b-catenin signaling and consequent reduction of cell proliferation or invasion in colorectal cancer [42], pancreatic cancer [26], cervical SCC [34], endometrial cancer [43] and renal cell carcinoma [44]. DKK3 over-expression also activates c-Jun N-terminal kinase (JNK) and induces apoptosis in glioma [30], bladder cancer [45], prostate cancer [25], testicular cancer [31], and NSCLC [46]. Based on these convincing studies, DKK3 is considered to be a potential therapeutic target. The most promising approach for DKK3-targeted cancer therapy is intra-tumoral injection of an
Please cite this article as: Katase N et al., DKK3 expression and function in head and neck squamous cell carcinoma and other cancers, Journal of Oral Biosciences, https://doi.org/10.1016/j.job.2020.01.008
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Fig. 1. The Wnt/b-catenin signaling pathway and its inhibition by DKK family. The binding of Wnt ligand to its receptor, Frizzled and LRP5/6 leads to the stabilization of b-catenin and, consequently, the transcription of its target genes. DKK family members (DKK1, 2, and 4) bind to LRP5/6 and Kremen, and inhibit Wnt/b-catenin signaling by sequestration of Wnt receptors. DKK3 does not bind to LRP5/6; instead, its cytoplasmic isoform, DKK3b, inhibits the nuclear translocation of b-catenin.
adenovirus vector carrying REIC/DKK3 gene (Ad-REIC), with an aim to initiate re-expression of the DKK3 gene in DKK3 defeated malignant tissues. It was reported that adenovirus-mediated fulllength DKK3 cDNA expression successfully exerts anti-cancer effects in the subcutaneous xenograft models of prostatic [25], testicular [31], and breast cancers [47] and orthotopic cancer models of prostate cancer [48], malignant mesothelioma [47], and scirrhous gastric carcinoma [49]. Moreover, ad-REIC significantly suppressed cancer cell proliferation and increased apoptosis, it has also been suggested that ad-REIC may also activate anticancer immunity [50]. Now, ad-REIC research is addressing its clinical application for cancer treatment. A Phase I/IIa in situ Ad-REIC gene therapy trial for prostate cancer is ongoing (UMIN000004929; NCT01931046). In addition, direct and systemic anticancer effects have been detected in a patient with metastatic castration-resistant prostate cancer [51]. However, there are some controversial reports for ad-REIC treatment. Some reports have suggested that over-expression of DKK3 may not cause apoptosis or affect cellular proliferation of cancer cells, either by transient overexpression or stable overexpression of DKK3 [8,31,52e55]. Zenzmaier and colleagues have hypothesized that reported anti-proliferative or pro-apoptotic effects of DKK3 over-expression, as a result of the unfolded protein response, are in vitro artifacts that do not reflect the biological role of the endogenous DKK3 protein [55]. Although DKK3 may be a promising anticancer target, further investigation is needed to examine the possibility of Ad-REIC gene therapy.
4. Oncogenic functions of DKK3 in HNSCC and other cancers As mentioned above, DKK3 shows obvious tumor suppressive functions in several cancers. Nevertheless, DKK3 function in HNSCC is completely different and indicates complex oncogenic function. We first identified the DKK3 gene as a HNSCC-specific tumorassociated gene by LOH analysis [3]. LOH analysis is a sensitive method to detect microdeletions in specific regions on the
chromosome and is critical for the identification of tumor suppressor genes (TSG) [4]. We found that chromosomal loci, including DKK3 (11p15.2), are frequently deleted in HNSCC cancer tissue; thus, we initially identified DKK3 as a TSG. However, a DKK3-LOH (þ) status is correlated with less lymph node metastasis and favorable overall survival [3]. Therefore, we next investigated the protein expression of DKK3 by immunohistochemistry in HNSCC and precursor lesions. The results showed that DKK3 expression was low and membranous in normal tissue, however, it increased in epithelial dysplasia and cancers with cytoplasmic expression [5]. Interestingly, DKK3 protein expression was observed in more than 84% of the 90 cases of HNSCC tissue samples, and survival analysis showed that the DKK3 () patients exhibited significantly longer disease-free survival rates, metastasis-free survival rates, and longer overall survival rates [6]. These results led us to hypothesize that DKK3 may possess oncogenic function specifically in HNSCC, and we thus investigated the effects of transient knockdown of DKK3 by siRNA in HNSCC cells. Supporting our hypothesis, the siRNA transfection did not affect cell proliferation, however, it significantly decreased cell migration and invasion by signaling pathways other than Wnt/bcatenin signaling [7]. To investigate the detailed mechanism by which DKK3 exerts oncogenic function in HNSCC, we established an over-expression model by transfection of a full-length DKK3 expressing plasmid and a stable knockdown model by infection of a lentivirus carrying specific shRNA targeting DKK3. The over-expression of DKK3 resulted in significantly elevated cellular proliferation, migration, invasion and in vivo tumor growth, together with significantly increased Wnt target genes including MYC and CCND1. However, the TCF/LEF activity was not changed by DKK3 transfection, implying that these elevated malignant potentials by DKK3 may not be caused by Wnt/b-catenin signaling. Microarray and western blotting analyses revealed that DKK3 augmented the malignancy of HNSCC cells by increasing the phosphorylation of AKT [8]. Moreover, the stable knockdown of DKK3 significantly decreased cellular proliferation, migration, invasion and in vivo
Please cite this article as: Katase N et al., DKK3 expression and function in head and neck squamous cell carcinoma and other cancers, Journal of Oral Biosciences, https://doi.org/10.1016/j.job.2020.01.008
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Fig. 2. Gene sequence of DKK3 and the corresponding protein sequence. The start codons are indicated in red. The start codon with an asterisk (*) indicates the start codon for DKK3b. The signal peptide is indicated in blue, and cysteine rich domains (Cys-1 and Cys-2) are indicated by green and yellow lines, respectively. The predicted coiled-coil structure is underlined.
Please cite this article as: Katase N et al., DKK3 expression and function in head and neck squamous cell carcinoma and other cancers, Journal of Oral Biosciences, https://doi.org/10.1016/j.job.2020.01.008
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66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 Fig. 3. Prospective role of DKK3 in HNSCC. All of our data suggest that DKK3 may bind to some receptors and activate Akt via PI3K/PDK1 and via the activation of the mTOR complex 89 by the DKK3b/bTrCP-mediated degradation of DEPTOR. 90 91 92 mechanisms underlying DKK3 function in different tumor cell tumor growth. The combination of microarray analysis, pathway 93 environments. analysis and western blotting analysis demonstrated that levels of 94 phosphorylated AKT, PI3K, PDK1 and total p38 MAPK were reduced. 95 Furthermore, phosphorylation of mTOR was slightly decreased in 96 5. Conclusions HSC-3 shDKK3 cells, which may be due to the increased expression 97 of DEPTOR. Conversely, DKK3 over-expression in DKK3 knockdown 98 DKK3 is a very interesting molecule that may behave as an cells improved cellular proliferation, migration, and invasion with 99 oncogene or tumor suppressor gene, depending on the cellular elevation of phosphorylated AKT and p38 MAPK signaling [9]. 100 context and cancer type. In either case, there is a plethora of inBased on the results, we predicted that DKK3 may modulate cancer 101 formation now available that highlights how DKK3 is an obvious cell malignant potentials by activating AKT thorough the binding of 102 candidate therapeutic target for cancer therapy. DKK3 to receptors and by intracellular protein-protein interactions 103 of DKK3b (Fig. 3). 104 Our investigations strongly suggest an oncogenic function of 105 Ethical approval DKK3. Moreover, we investigated the correlation between DKK3 106 expression and patient prognosis in various kinds of malignancies 107 Ethical approval was not required for this review article. using databases provided by TCGA. Notably, high mRNA expression 108 levels of DKK3 were an unfavorable prognostic marker for HNSCC, 109 pancreatic and renal cancers, despite previous reports suggesting 110 Conflicts of interest the tumor suppressive role of DKK3. Conversely, high DKK3 mRNA 111 expression was associated with a favorable prognosis in prostate 112 The authors declare no competing interest. cancer, which is in accordance with a previous finding [9]. 113 This suggests that DKK3 may possess tumor- or tissue-specific 114 roles. Supporting our tentative theory, recent reports also suggest 115 Funding oncogenic roles of DKK3 in cancers. In fact, it is indicated that 116 30e50% of cancers in the liver, endometrium, ovary, lung, and 117 The work was supported by a Grant-in-Aid for Scientific brain are DKK3-positive [36,56,57], and oncogenic effects of DKK3 118 Research (C) from the ministry of Education, Culture, Sports, Scihave been reported even in cancers other than HNSCC [57e59]. In 119 ence and Technology (Japan Society for the Promotion of Science, lung adenocarcinoma, DKK3 positive cases show more progressive 120 KAKENHI Grant no. 16K11470 to NK) and the Takeda Science tumor stages and metastatic statuses, and DKK3-knockdown in Foundation (grant no. 2018047114 to NK). Q2 121 lung adenocarcinoma cells shows less invasive phenotypes [57]. 122 Up-regulation of DKK3 in esophageal squamous cell carcinoma 123 (ESCC) has been reported [60], and very recently, Kajiwara and 124 CRediT authorship contribution statement colleagues have reported that DKK3 is expressed in approximately 125 50% of ESCC tissues, and simultaneous expression of DKK3 and 126 Naoki Katase: Conceptualization, Data curation, Formal analCKAP4 was associated with a poor prognosis [61]. Moreover, 127 ysis, Funding acquisition, Validation, Writing - original draft, stromal expression of DKK3 is reported to be associated with 128 Writing - review & editing. Kenichi Nagano: Validation, Writing aggressive breast, colorectal, and ovarian cancers [62]. Thus, going 129 review & editing. Shuichi Fujita: Validation, Writing - review & forward, it will be important to investigate the molecular 130 editing. Please cite this article as: Katase N et al., DKK3 expression and function in head and neck squamous cell carcinoma and other cancers, Journal of Oral Biosciences, https://doi.org/10.1016/j.job.2020.01.008
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Acknowledgements We thank Dr. Shin-ichiro Nishimatsu (Department of Natural Sciences, Kawasaki Medical School), Dr. Akira Yamauchi (Department of Biochemistry, Kawasaki Medical School) and Dr. Masahiro Yamamura (Department of Clinical oncology, Kawasaki Medical School) for their collaboration in our works. References [1] Bailey MH, Tokheim C, Porta-Pardo E, Sengupta S, Bertrand D, et al. Comprehensive characterization of cancer driver genes and mutations. Cell 2018;173:371e5. [2] Sanchez-Vega F Mina M, Armenia J, Chatila WK, Luna A, et al. Oncogenic signaling pathways in the cancer genome atlas. Cell 2018;173:321e37. [3] Katase N, Gunduz M, Beder LB, Gunduz E, Lefeuvre M, Hatipoglu OF, Borkosky SS, Tamamura R, Tominaga S, Yamanaka N, Shimizu K, Nagai N, Nagatsuka H. Deletion at Dickkopf (Dkk-3) locus (11p15.2) is related with lower lymph node metastasis and better prognosis in head and neck squamous cell carcinoma. Oncol. Res. 2008;17:273e82. [4] Katase N, Gunduz M, Beder LB, Gunduz E, Al Sheikh Ali M, Tamamura R, Yaykasli KO, Yamanaka N, Shimizu K, Nagatsuka H. Frequent allelic loss of dkk-1 locus (10q11.2) is related with low distant metastasis and better prognosis in head and neck squamous cell carcinomas. Canc. Invest. 2010;28: 103e10. [5] Fujii M, Katase N, Lefeuvre M, Gunduz M, Buery RR, Tamamura R, Tsujigiwa H, Nagatsuka H. Dickkopf (Dkk)-3 and b-catenin expressions increased in the transition from normal oral mucosal to oral squamous cell carcinoma. J. Mol. Histol. 2011;42:499e504. [6] Katase N, Lefeuvre M, Gunduz M, Gunduz E, Beder LB, Grenman R, Fujii M, Tamamura R, Tsujigiwa H, Nagatsuka H. Absence of Dickkopf (Dkk)-3 protein expression is correlated with longer disease free survival and lower incidence of metastasis in head and neck squamous cell carcinoma. Oncol Lett 2012;3: 273e80. [7] Katase N, Lefeuvre M, Tsujigiwa H, Fujii M, Ito S, Tamamura R, Buery RR, Gunduz M, Nagatsuka H. Knockdown of Dkk-3 decreases cancer cell migration and invasion independently of the Wnt pathways in oral squamous cell carcinoma-derived cells. Oncol. Rep. 2013;29:1349e55. [8] Katase N, Nishimatsu S, Yamauchi A, Yamamura M, Terada K, Itadani M, Okada N, Hassan NMM, Nagatsuka H, Ikeda T, Nohno T, Fujita S. DKK3 overexpression increases malignant property of head and neck squamous cell carcinoma cells. Oncol. Res. 2018;26:45e58. [9] Katase N, Nishimatsu S, Yamauchi A, Yamamura M, Fujita S. DKK3 knockdown confers negative effects on malignant potency of head and neck squamous cell carcinoma cells via PI3K/Akt signal and MAPK pathways. Int. J. Oncol. 2019;54:1021e32. [10] Katase N, Nohno T. DKK3 (dickkopf 3 homolog (Xenopus laevis)). Atlas Genet Cytogenet Oncol Haematol 2013;17:678e86. [11] Veeck J, Dahl E. Targeting the Wnt pathway in cancer: the emerging role of Dickkopf-3. Biochim. Biophys. Acta 2012;1825:18e28. [12] Klaus A, Birchmeier W. Wnt signalling and its impact on development and cancer. Nat. Rev. Canc. 2008;8:387e98. [13] Niehrs C. Function and biological roles of the Dickkopf family of Wnt modulators. Oncogene 2006;25:7469e81. [14] Tortelote GG, Reis RR, de Almeida Mendes F, Abreu JG. Complexity of the Wnt/ b-catenin pathway: searching for an activation model. Cell. Signal. 2017;40: 30e43. [15] Chien AJ, Conrad WH, Moon RT. A Wnt survival guide: from flies to human disease. J. Invest. Dermatol. 2009;129:1614e27. [16] Mao B, Wu W, Li Y, Hoppe D, Stannek P, Glinka A, Niehrs C. LDL-receptorrelated protein 6 is a receptor for Dickkopf proteins. Nature 2001;411:321e5. [17] Bafico A, Liu G, Yaniv A, Gazit A, Aaronson SA. Novel mechanism of Wnt signalling inhibition mediated by Dickkopf-1 interaction with LRP6/Arrow. Nat. Cell Biol. 2001;3:683e6. [18] Fujii Y, Hoshino T, Kumon H. Molecular simulation analysis of the structure complex of C2 domains of DKK family members and b-propeller domains of LRP5/6: explaining why DKK3 does not bind to LRP5/6. Acta Med. Okayama 2014;68:63e78. [19] Leonard JL, Leonard DM, Wolfe SA, Liu J, Rivera J, Yang M, Leonard RT, Johnson JPS, Kumar P, Liebmann KL, Tutto AA, Mou Z, Simin KJ. The Dkk3 gene encodes a vital intracellular regulator of cell proliferation. PloS One 2017;12: e0181724. [20] Maehata T, Taniguchi H, Yamamoto H, Nosho K, Adachi Y, Miyamoto N, Miyamoto C, Akutsu N, Yamaoka S, Itoh F. Transcriptional silencing of Dickkopf gene family by CpG island hypermethylation in human gastrointestinal cancer. World J. Gastroenterol. 2008;14:2702e14. [21] Tsuji T, Miyazaki M, Sakaguchi M, Inoue Y, Namba M. A REIC gene shows down-regulation in human immortalized cells and human tumor-derived cell lines. Biochem. Biophys. Res. Commun. 2000;268:20e4. [22] Nozaki I, Tsuji T, Iijima O, Ohmura Y, Andou A, Miyazaki M, Shimizu N, Namba M. Reduced expression of REICDKK3 gene in non-small cell lung cancer. Int. J. Oncol. 2001;19:117e21.
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Please cite this article as: Katase N et al., DKK3 expression and function in head and neck squamous cell carcinoma and other cancers, Journal of Oral Biosciences, https://doi.org/10.1016/j.job.2020.01.008
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