MKP-1 signaling axis in oral cancer: Impact of tumor-associated macrophages

Oral Oncology 103 (2020) 104591

Contents lists available at ScienceDirect

Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology

Review

The p38/MKP-1 signaling axis in oral cancer: Impact of tumor-associated macrophages

T

Zhenning Lia,b,c, , Fa-yu Liua,c, Keith L. Kirkwoodc,d, ⁎⁎

⁎

a

Department of Oromaxillofacial-Head and Neck Surgery, School and Hospital of Stomatology, China Medical University, Liaoning Province Key Laboratory of Oral Disease, Shenyang, China b Department of Medical Genetics, China Medical University, Shenyang, China c Department of Oral Biology, School of Dental Medicine, University at Buffalo, Buffalo, NY, USA d Department of Head and Neck/Plastic and Reconstructive Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA

ARTICLE INFO

ABSTRACT

Keywords: Oral cancer MKP-1 Tumor microenvironment p38 mitogen activating kinases Tumor-associated macrophages

Oral squamous cell carcinomas (OSCC) constitute over 95% of all head and neck malignancies. As a key component of the tumor microenvironment (TME), chronic inflammation contributes towards the development, progression, and regional metastasis of OSCC. Tumor associated macrophages (TAMs) associated with OSSC promote tumorigenesis through the production of cytokines and pro-inflammatory factors that are critical role in the various steps of malignant transformation, including tumor growth, survival, invasion, angiogenesis, and metastasis. The mitogen-activated protein kinases (MAPKs) can regulate inflammation along with a wide range of cellular processes including cell metabolism, proliferation, motility, apoptosis, survival, differentiation and play a crucial role in cell growth and survival in physiological and pathological processes including innate and adaptive immune responses. Dual specificity MAPK phosphatases (MKPs) deactivates MAPKs. MKPs are considered as an important feedback control mechanism that limits MAPK signaling and subsequent target gene expression. This review outlines the role of MKP-1, the founding member of the MKP family, in OSCC and the TME. Herein, we summarize recent progress in understanding the regulation of p38 MAPK/MKP-1 signaling pathways via TAM-related immune responses in OSCC development, progression and treatment outcomes.

Introduction to oral cancer and the tumor microenvironment Oral squamous cell carcinoma (OSCC) is the most prevalent pathological form of head and neck malignancy, in both emerging and established countries [1–2]. Head and neck cancers are highly inflammatory in nature. This is reflected in risk factors typically associated with OSCC which include smoking, alcohol, human papillomavirus status, and oral habits, such as betel quid and tobacco chewing [3–4]. Furthermore, chronic inflammatory-like oral lesions show some degree of malignant potential in association with OSCC development, including leukoplakia, erythroplakia, lichen planus and submucous fibrosis [5]. Additional metanalyses reveals a positive association between periodontal disease and risk of oral cancer supporting the interaction of chronic inflammation and oral cancer progression [6]. These risk factors imply that oral inflammation is a major component of OSCC progression.

Oral cancer diagnoses rely heavily upon physical examination, radiographic imaging, and pathological examination [7]. Surgical resection remains the treatment of choice for OSCC since surgery permits accurate pathologic staging, information about the marginal status and tumor spread characteristics through histopathologic features which informs subsequent management based upon assessment of risk versus benefit [8]. Subsequent OSCC regimens in these patients, such as adjuvant radiotherapy, with or without chemotherapy, are usually decided by depth of invasion, status of tumor margins, and other histopathologic characteristics [9]. Despite advances in diagnoses, surgical and oncological management of OSCC, overall 5-year survival rate for OSCC patients was still approximately 50% for the past three decades [10–11]. While OSCC have always been thought as gene-related diseases, the molecular, genetic and immunoregulatory mechanisms of OSCC carcinogenesis remains unclear [12–13]. Since chronic inflammation is generally associated with poorer prognoses [14], it is

⁎ Corresponding author at: Department of Oral Biology, School of Dental Medicine, University at Buffalo, The State University of New York, 645 Biomedical Research Building, 3435 Main St., Buffalo, New York 14214-8006, United States. ⁎⁎ Corresponding author at: Department of Oromaxillofacial-Head and Neck Surgery, School and Hospital of Stomatology, China Medical University, Liaoning Province Key Laboratory of Oral Disease, Shenyang, China. E-mail address: [email protected] (K.L. Kirkwood).

https://doi.org/10.1016/j.oraloncology.2020.104591 Received 26 January 2020; Accepted 4 February 2020 1368-8375/ © 2020 Published by Elsevier Ltd.

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essential to understand how the tumor microenvironment is engaged during OSSC progression. The interplay between tumors and their immunologic microenvironment is complex and difficult to decipher. Related to oral cancer progression, the tumor microenvironment (TME) has been shown to have a decisive prognostic role. This is likely due to the site-specific molecular crosstalk between the cancer cells and the TME. Studies addressing the cell signaling deregulation within the TME have only recently been described in OSCC. In this review, we present current evidence for the role p38 mitogen-activated protein kinases (MAPK) and the negative regulator of p38 MAPK activity, MAPK phosphatase (MKP)-1, with insights into control of inflammation associated with oral cancer tumor progression. Understanding the TME should reveal a broader perspective for emerging cancer therapies.

occur through all phases of the OSCC process, from early tumorigenesis to tumor progression and metastasis [15]. The TME is composed of a multitude of cell types, including local stromal cells such as resident stromal fibroblasts, and distant recruited cells, including endothelial cells, immune cells, including myeloid and lymphoid cells as well as circulating platelets [15]. These subgroups of cells are interwoven with each other as well as tumor cells through complex communication networks that supply numerous cytokines, chemokines, growth factors and proteins of the extracellular matrix (ECM), such as transforming growth factor β (TGF-β), vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF), M−CSF, IL-10 and chemokine C-X-C motif ligand (CXCL) [22–23]. Tumor-associated macrophages in oral cancer

The tumor inflammatory infiltrate in oral cancer

Over the past several years, several studies have reported that macrophages comprise up to 50% of malignant solid tumors mass and play a decisive role in tumor infiltrating immune cells [24–26]. The tumor environment has both immature and adaptive immune cells where key roles of tumor-associated macrophages (TAMs) and T-lymphocytes have been well described, respectfully [27]. The majority of TAMs associated with tumor immunology differentiate from bone marrow-derived monocytes [28]. TAMs display great versatility as immune cells since they produce diverse factors in the TME that can either promote or inhibit tumor progression [29]. TAMs have been shown to regulate cancer-related inflammation, immune escape, matrix remodeling, and cancer metastases [30]. Additionally, there are also diverse molecular targets and signaling pathways activated by TAMs that are related with tumorigenesis processes including proliferation, apoptosis, invasion, migration and angiogenesis [31]. During normal physiological responses to infection or injury, myeloid cells including monocytes and macrophages are key elements which regulate tissue homeostasis and local inflammation/immunity. Monocytes exist as the secondary recruited effectors of the acute inflammatory response after neutrophils and also migrate to the site of tumor microenvironment, guided by chemotactic factors. It is accepted that monocytes, in the presence of granulocyte–macrophage colony stimulating factor (GM-CSF) and interleukin (IL)-4, differentiate into immature dendritic cells (DCs). DCs migrate into inflamed peripheral tissue where they capture antigens and, after maturation, migrate to lymph nodes to stimulate T-lymphocyte activation. Soluble factors such as IL-6 and M−CSF, derived from neoplastic cells, push myeloid precursors towards a macrophage-like phenotype [32]. Unlike macrophages in non-cancerous tissues, TAMs are modified by the tumor milieu, losing some of their phagocytic capacity and ability to effectively present antigens to T-cells [33]. As such, TAMs characteristically display cellular plasticity in response to local microenvironmental stimuli [34]. In vitro, macrophages can be divided into two subgroups: classically activated M1 and alternatively activated M2 subtypes [35–36]. M1 macrophages are innate immune cells which have the function of killing tumor cells by reactive oxygen species and nitrogen intermediates that direct tumor cell death [37]. The secretory products of M1 macrophages include: IL-1β, IL-6, TNFα, CCL5, CXCL9, CXCL10, IL-12, IL-23. In contrast, M2 macrophages located in the tumor stroma secrete tumor promoting cytokines including IL-10, TGF-β, IL13, IL-1 receptor antagonist [22–23,38]. Although M2 macrophages have been associated with shorter survival times and poorer clinical outcome by promoting tumor progression, TAMs are still comprised of both M1 and M2 macrophages [39–41]. In fact, other studies have implied that M1-like tumor-associated macrophages activated by exosome can promote malignant migration in OSCC [38]. Thus, macrophages are functionally heterogeneous cells that are influenced by numerous signals within the TME that can instruct TAM polarization and thus potentially influence OSCC progression.

An association between the cancer progression and inflammation has long been appreciated [15]. While the genetic changes that occur within cancer cells, such as activated oncogenes or dysfunctional tumor suppressors, are responsible for many aspects of cancer development, they are not sufficient to maintain tumor growth. Tumor promotion and progression are dependent on additional processes provided by cells within the TME that are not cancerous per se. Inflammation is key component of a complex biological process by which immune system reacts to harmful stimuli, such as pathogens, damaged cells, toxic compounds, or irritants, and is a protective response involving immune cells, blood vessels, and molecular mediators [15]. Indeed, nearly 25% of all cancers are etiologically linked to chronic inflammation and infection [16]. During the normal inflammatory response, protective chemokines and cytokines mediate leukocyte chemotaxis from general circulation to damage sites to facilitate the local immune response and repair damaged tissues [17]. However, prolonged inflammation contributes to the development including cardiovascular and bowel diseases, diabetes, arthritis, and cancer [18]. In the oral microenvironment, periodontal disease (gum disease) represents the most common form of chronic oral inflammation that results in local tissue and bone destruction causing eventual tooth loss. Indeed, epidemiological data supports the association between periodontal disease and OSCC [6]. However, the mechanistic data to support these association studies are notably lacking. However, it can be appreciated that well-established periodontal pathogens, particularly Porphymonas gingivalis (P. gingivalis) and Fusobacterium nucleatum, can potentially promote oral cancer as well as non-oral cancers including colorectal cancer. In the case of P. gingivalis, recent evidence indicates that this periodontal pathogen can enhance resistance to traditional chemotherapeutics, including paclitaxel, in OSCC murine xenograft models as well as promoting an invasive phenotype through in vitro studies. Besides specific periodontal pathogens, several investigators have sought to address the potential causal role of alternations in the oral microbiome and oral cancer [19–20]. However, this is an area of active investigation without definitive evidence to support a direct causal role [21]. In another recent study, periodontal inflammation was shown to increase lymph node metastasis using a syngeneic breast cancer model where greater tumor burden was observed compared to controls. Collectively, these studies support the concept that the oral cavity niche and possibly periodontal pathogens create an ideal tumorpromoting microenvironment for OSCC progression. Significant evidence indicates that oral tumors exist as a complex of the transformed tumor cells complexed with other cells that constitute the oral TME associated with OSCC [22]. The inflammatory infiltrate along with the mediators they secrete into the TME play an essential role in the formation of a suitable TME for tumor cell expansion. Inflammation can be derived from intrinsically from tumor cells themselves or from extrinsically acquired tumor-infiltrating immune cells. These intrinsic and extrinsic mechanisms of inflammation generation 2

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MAPK/MKP signaling pathways in tumor-associated macrophage polarization

ERK activating promote cell progression, migration, proliferation, cell survival and metastasis [53,66,69,76,111,116]. ERK1/2 suppression inhibit MMP-9 expression, cell metastasis and decrease proliferation [67–68]. JNK phosphorylation involved in apoptosis and autophagy [63] IL-8 is the major stimulus of inflammatory mediation in OSCC progression and migration by reducing JNK [57]. Downregulating JNK1/2 inhibit MMP-9 and MMP-2, and suppress invasion and metastasis [67,74] JNK activation decrease E–cadherin and increase Vimentin in metastasis [5 7 ]. JNK suppression inhibited bortezomib induction of autophagy regulatory proteins and autophagosome formation [71]. JNK activation is associated with cetuximab resistance [61]. JNK suppression increasing toxicity and inhibit Erlotinib induced IL-6 and enhance tumor response to EGFRIs [77].

Promote

Inhibit Promote

Increased [57,65,72]

Decreased [57,70] Increased [57]

ERK 1/2

JNK 1/2/3

EGFR-RAS-MEKMAPK-ERK [114] EGFR/MAPK/ AP1 [59] IL6,IL8 [109] Unknown

Increase of activated ERK1/2 was associated with moderately or poorly differentiated grade, early-stage carcinogenesis and shorter overall survival [65–66,115].

Mitogen-activated protein kinase (MAPK) signaling cascades play fundamental roles in many immune response processes and function as master regulators of macrophage pro- and anti-inflammatory cytokine production that have profound effects on tumor biology. There are 3 distinct families of MAPKs: the p38 MAP kinases, the extracellular signalregulated protein kinases (ERK1/2) and the c-Jun NH2-terminal kinases (JNK1, JNK 2, and JNK 3). They are encoded by independent genes and have unique cell-specific functions. All of these MAPKs act to phosphorylate targets at serine or threonine residues and less commonly tyrosine. Activated MAPK kinases can phosphorylate MAPKs at the tripeptide motif Thr-Xaa-Tyr. The amino acid denoted X corresponds to glutamic acid in ERK, proline in JNK or glycine in p38. All the subtypes are isogeneic and are activated through the dual phosphorylation of tyrosine (Tyr) and threonine (Thr) residues in conserved Thr-X-Tyr motif mediated by the MAPK [42]. Upon stimulation by extracellular stresses or ligands, MAPKs act as intracellular signaling mediators that control cell differentiation, proliferation, apoptosis, and other effector functions. Activation of the MAPKs can initiate the inflammatory response by phosphorylation and activation MAPK-dependent transcription factors, including ELK-1, cJun, ATF-2, and CREB [43] along with phosphorylation of RNA binding proteins [44] to control target gene expression for several macrophage activities, such as cellular growth and differentiation, inflammatory responses and polarization. The evidence that MAPK signaling is important for macrophage polarization has been recently been shown. The p38 and ERK1/2 pathways are engaged in M2 TAM repolarization. Using a copper chelator, M2 TAMs were shifted towards an M1 phenotype through activation of p38 MAPK which increased IL-12 production and the activation of ERK1/2 was found responsible for IFN-γ production by TAMs which prolonged IL-12 production and downregulated TGF-β production thus reprogramming regulatory cytokine production by TAMs [45]. Activation the p38 and ERK signaling pathways may induce IL-8 production from M2 macrophages which promoted the migration and invasion in breast cancer [46]. Another study showed that p38 MAPK signaling pathway was involved in acquisition of M2 markers macrophages subjected to IL-4 stimulation [47]. More recently, the p38 MAPK immediate downstream kinase, MAPKAPK-2 (or MK2) was shown to be needed for M2 TAMs using a globally deficient MK2 mouse model. Here, M1 macrophages were enhanced compared to wild-type controls in a colon cancer model [48]. Other groups have addressed the roles of ERK signaling in M1/M2 polarization that suggests that ERK, like p38 MAPK, is needed for M2 TAM expansion [49]. Reduced levels DUSP1 expression can alter polarization state in M2 macrophages through prolonged ERK1/2, p38 and JNK activation in hepatocellular carcinoma [50]. We have found increased M2 macrophage polarization in DUSP1 deficient mice using a chemical carcinogen model of OSCC, implying that DUSP1 deficiency enhances tumor-associated inflammation [51]. In this model, both phosphorylated levels of p38 and ERK were higher compared with wild-type control OSSC tissues. Taken jointly, these studies suggest that ERK1/2, p38 and JNK activation may play a decisive role in TAM M2 polarization.

Decreased in OSCC patient tissues [57,70]

P38 activation increase MMP-9, promote cell proliferation, migration, invasion, promote EMT and contribute to the secretion of pro-angiogenic cytokines, VEGF and IL-6 [62,64,53–56]. p38 suppression reduce cell migration, invasion, proliferation apoptosis, autophagy, increase DNA damage and induce G2/M arrest [60,68,107]. p38 α activation promote tumorigenesis [113]. p38 α suppression, inhibits cell growth and induces [88].

p38- inhibited cells showed chemosensitivity to cisplatin, with increased apoptotic population after treatment with increasing concentration of cisplatin [107]. Radiation induced the phosphorylation of p38 MAPK, resulting in enhanced tumor cell migration [112]. p38α MAP kinase inhibitor can be a potential therapeutic agent for human oral cancer [59,113]. ERK activation increase multidrug chemoresistance [53]. Radiation induce phosphorylation of ERK, resulting in enhanced cell migration [112]. Increased expression in tumor margins associated with recurrence [107]. Down-expression in low grade carcinoma, and up- expression in high grade carcinomas [56]. Increased expression is associated with earlystage carcinogenesis [111]. p38 α, β, γ, δ expression elevated in serum of HNSCC patients [59,108]. IL-6, IL8 [109–110] Promote Increased [17,57,107–108] p38 (α, β, γ, δ)

Molecular Targets Carcinogenesis Expression (tumor/ Normal tissue) MAPKs

Table 1 Summary of MAPKs in Oral Squamous Cell Carcinoma Tumor Biology.

Survival and Clinical Outcomes

Impact on Oncological Therapies

Biological Function in OSCC

Z. Li, et al.

MAPK activation in OSCC As stated above, MAPKs can regulate inflammation and a wide range of cellular processes, including cellular metabolism, proliferation, motility, apoptosis, survival, and differentiation in addition to their crucial role in innate and adaptive immune responses. The MAPK phosphatases (MKPs), also known as dual-specificity phosphatases (DUSPs), belong to a protein family in mammalian cells which can negatively regulate the MAPK activities [52]. Importantly, epigenetic 3

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and genetic regulatory factors increase cellular stimulation through multiple mechanisms, such as oxidative stress, growth factors, cytokines, that can result in DNA damage and/or DNA methylation, which will activate MAPK pathways directly. Multiple lines of evidence in OSCC have reported that active (the phosphorylated form) of p38 MAPK can promote cell proliferation, migration and invasion [53–56]. Consistent with these protumorigenic roles, expression levels of phosphorylated forms of both p38 MAPK and ERK were higher in OSCC patient tissues than in non-cancerous matched tissues [57]. (Table 1) One seminal study revealed that phosphorylated p38 MAPK was found in 79% of the human head and neck squamous cell carcinoma (HNSCC) cases, compared with the expression of phosphorylated ERK 1/2(p-ERK1/2) and JNK (p-JNK) were only in 33% and 16% of the samples, respectively [55]. These data implied that phosphorylated p38 MAPK might have a close relationship with OSCC. They also found that the activation of p38 has a remarkable relationship with poorly differentiated carcinoma which implied a bad prognosis [58]. In vitro and in vivo data support that concept that if p38 signaling was blocked, OSCC tumor have reduced proliferative capacity. Moreover, angiogenesis and lymphangiogenesis were also reduced in tumors where p38 was inhibited [55]. In addition, p38α is over-expressed in peripheral blood mononuclear cells of OSCC patients suggesting that it may play a role in the progression of OSCC [59]. Finally, using the TCGA database (http://ualcan.path.uab.edu/index.html), p38 (encoded by MAPK14) was measured in human samples where there is currently 44 normal tissues and 520 primary tumors in head and neck in this database. The results revealed that there was significantly higher expression of MAPK14 mRNA in primary head and neck tumor compared with normal tissues (See Figure 1). There was also significant difference between normal tissue and primary head neck tumor in individual cancer stages, patient’s race, patient’s gender, patient’s age, tumor grade, HPV status and nodal metastasis status (data not presented). Inhibition of p38 MAPK and activation of JNK can induced G2/ M arrest, apoptosis, and autophagy [60]. Related to OSCC, p38 signaling inhibition resulted in reduced proliferation rates, with reduced tumor-induced inflammation [61–62] However, there are also some studies that reported p38 may function as a tumor-suppressor gene where increase in phosphorylation of p38 MAPK and JNK was involved

in apoptosis and autophagy [63]. Activation of p38 led to decreased cell proliferation and increased secretion of pro-angiogenic cytokines, VEGF, IL-6 and IL-8 in OSCC [64]. The expression of activated ERK1/2 was significantly stronger in OSCC of the tongue compared to normal oral mucosa [65–66]. Downregulating ERK1/2 signals pathways was observed to suppress cellular proliferation, inhibit MMP-9 expression, and OSCC cell metastasis [67–68]. Activating ERK appears to promote cell progression, migration, proliferation and metastasis [66,69]. The role of JNK signaling in OSCC is complex and in most cases remains controversial. It is reported that the expression of p-JNK was lower in HNSCC patient tissues than in non-cancerous matched tissues, and reducing JNK can promote cell progression and migration [57,70]. Activation of JNK induced G2/M arrest, apoptosis, and autophagy in human nasopharyngeal cancer [60]. Downregulating JNK1/2 pathways inhibited MMP-9 expression and oral cancer cell metastasis [57,67]. Additionally, it has been shown that an increase in phosphorylation of JNK involved in apoptosis and autophagy in OSCC [63]. IL-8 is the major stimulus of inflammatory mediation in OSCC progression and migration by activating the p38 MAPK/ERK-NF-κB pathway and reducing JNK [57]. Pharmacologic inhibition of JNK dramatically inhibited bortezomib induction of autophagy regulatory proteins and autophagosome formation [71]. However, other studies reported that suppressed protein expression of phosphorylated JNK displayed inhibitory effects on metastatic ability of CAL-27 oral cancer cells [72]. After activation, JNK promoted E‑cadherin low expression and Vimentin high expression which will promote in OSCC metastasis [73]. ROS, as an oncogene, knockdown could decrease the phosphorylation of JNK in OSCC [74]. Stimulation of SCC4 cells with IL-6, which can increase migration in OSCC, resulted in timedependent phosphorylation of JNK [75]. Pharmacological inhibition of ERK or JNK activity significantly suppressed the invasiveness of galectin-7-overexpressing cells and abrogated the upregulation of MMP-2 and MMP-9 [57,76]. Repression of JNK3 gene expression is essential for increasing PTX toxicity in OSCC [77]. As an additional layer of complexity, it appears that MAPK expression patterns can also be influenced by cytokines within the TME. For example, it was reported that IL-8 regulates inflammatory response by modulating the MAPK pathway in OSCC cells. IL-8 treatment could Fig. 1. p38/MAPK14 expression is increased in head and neck cancer tissues. Using data from TCGA database (http:// ualcan.path.uab.edu/index.html), MAPK14 gene expression was detected according to the sample types between 44 normal tissues and 520 primary tumors in head and neck. The results show a significantly higher lower expression levels of MAPK14 in primary head and neck tumors compared with normal tissues. (p = 2.02820000017034 X10-7).

4

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increase the level of p-p38 and p-ERK, but decrease the expression of pJNK in OSCC cells and then promotes migration of OSCC cells through increased MMP-2 and MMP-9 expression [57]. Thus, the overall role for MAPKs in OSCC progression maybe contextually defined and additional studies are warranted to help understand the roles of these critical signaling cascades.

results indicated that there was a significantly lower expression of DUSP1 in primary head and neck tumors compared with normal tissues. There was also significant difference between normal tissue and primary head neck tumor in individual cancer stages, patient’s race, patient’s gender, patient’s age, tumor grade, HPV status and nodal metastasis status (data not presented). These data suggest that the promoter methylation of DUSP1 gene might be a potential biomarker for oral malignancy as diagnostic and/or therapeutic targets in the future. The function of MKPs in OSCC has not been sufficiently studied and it appears that most studies have addressed how MKPs regulate different MAPKs related to cancer development (see Table 2).

MKP-1 repression in OSCC MKP-1, encoded in humans by DUSP1, was the first discovered of the MKP family members and thus the best studied to date. MKP-1 has been shown to be involved in various cellular functions, such as metabolic signaling, skeletal muscle function, inflammatory response and cancer. By dephosphorylating the threonine-glutamic acid-tyrosine motif on MAP kinases, MKP-1 can inhibit p38, ERK and JNK activation and subsequent signaling [78]. Therefore, MKP-1 is considered to be primary negative regulatory factor of MAPKs. A growing body of investigation suggests that epigenetic alterations, such as DNA methylation, histone covalent modifications, non-coding RNAs and chromatin remodeling, participate in the process of tumor progress, carcinogenesis and therapy resistance [79–80]. DNA methylation is controlled by DNA methyltransferases which will catalyze the transfer of the methyl group from S-adenosylmethionine to the cytosine in CpG dinucleotides at the 5-carbon (5-methylcytosine) [81]. The hypermethylation in the CpG islands on gene promoters will silence tumor suppressor genes and then promote tumorigenesis [82]. Epigenetic studies on DNA methylation profiling have revealed that the DUSP1 gene promoter is hypermethylated in nearly 88% of primary OSCC samples resulting in MKP-1 being reduced in expression [83–84]. We have shown that significant lower level of DUSP1 mRNA and MKP-1 protein expression in human HNSCC compared with adjacent normal tissue in a small cohort of OSCC samples [51]. Consistent with these data, we found within the TCGA data base the DUSP1 transcript numbers were significantly reduced expression in head and neck cancer tissues compared with the normal tissue expression (see Figure 2). According to the data from TCGA database (http://ualcan.path.uab. edu/index.html), DUSP1 gene expression was detected in 44 normal tissues and 520 primary tumors in head and neck tissue samples. The

Therapeutic reprograming of the p38 /MKP-1 signaling axis in oral cancer p38 MAPK regulates the production of cytokines in the TME and promotes cancer cells to survive despite oncogenic stress, radiotherapy, chemotherapy, and targeted therapies [59]. Accordingly, p38 MAPK plays an important role in key cellular processes related to inflammation and cancer. In OSCC cells where p38 was inhibited, these cells showed increased chemosensitivity towards cisplatin, along with an increased apoptotic population after treatment in OSCC [85–86]. Other studies implied that SB203580, a classic inhibitor of p38 MAPK, suppressed erlotinib-induced IL-6, which enhanced OSCC tumor response to EGFR inhibitors in OSCC [87]. Another p38α inhibitor was shown reduce to cell growth and induce apoptosis in an oral cancer cell line [88]. Additionally, a small peptide was developed as a promising anticancer agent targeting p38α MAPK [89]. Taken together, these findings provide a strong framework for p38 inhibitors to become potential novel molecular targets for adjuvant therapy in OSCC patients. Nevertheless, none of the small molecule p38 inhibitors have advanced completely through human clinical trials due of the significant systemic side effects of these small molecular inhibitors [90], suggesting that alternative strategies for p38 MAPK inhibition are necessary. MKP-1 appears to function as a tumor suppressor gene and maybe negatively regulated during oral cancer-associated inflammation [51,78]. Several strategies have been developed to increase MKP-1 expression as a novel anti-cancer therapeutic. An increase in MKP-1 Fig. 2. MKP-1/ DUSP1 expression is reduced in head and neck cancer tissues. According to the data from TCGA database (http://ualcan. path.uab.edu/index.html), DUSP1 gene expression was detected according to the sample types between 44 normal tissues and 520 primary tumors in head and neck. The results revealed that there was a significantly lower expression levels of DUSP1 in primary head and neck tumors compared with normal tissues. (p = 2.59019999893084 X 10-8).

5

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Unknown

ERK

Inhibit Decreased [69,129]

Unknown

Unknown

ERK Inhibit

Decreased [125–126]

Decreased [124] DUSP2/PAC1

DUSP4/MKP2

DUSP6/MKP3

DUSP5

Decreased [51,117–119] Increased [94,120–121] DUSP1/MKP1

Unknown

Unknown

ERK Inhibit

Down-regulation of DUSP2 increased overall survival [124].

level was found in mouse macrophages after treated with PDE4 inhibitor rolipram [91]. Another study also found that β2-receptor agonists salbutamol and terbutaline, as well as 8-Br-cAMP could increase MKP-1 expression, which seems to mediate, at least partly, the observed anti-inflammatory effects [92]. The cannabinoid receptor-2 (CB2R) also upregulated the expression level of MKP-1, which leads to the inhibition of MAPKs signaling pathway activation, especially for ERK and p38 [93]. In OSCC, increase of MKP-1 activity correlates with decrease of oral cancer radio-sensitivity [94–95]. Taken together, many types of MKP-1 agonists could be considered to be promising anti-tumor drug in OSCC therapy. There are several other agents that have been used to increase MKP-1 expression including dexamethasone and gold salts, such as auranofin, but none have been used in the context of oral cancer as a mono- or adjunctive therapy. In addition, as a cautionary note, not all cancers have reduced MKP-1 expression, suggesting that MKP-1 inhibitors may also have utility in other forms of cancer [96]. As an example of a class of therapeutics that can modulate MKP-1 expression, agonists of peroxisome proliferator-activated receptors (PPARs) have been used in several lines of both basic and clinical studies. PPARs are members of the nuclear hormone receptor superfamily, which function as ligand-dependent, sequence-specific activators of transcription. Three members of PPAR family were known as PPARα, PPARβ and PPARγ [97]. Multiple studies suggested PPARs, especially PPARγ, play an important role in modulating cell proliferation, differentiation and apoptosis [98]. Transcriptional activation of PPARγ receptor may cause decreased proliferation, metastasis and increased apoptosis [99]. One study that focused on OSCC revealed that PPARγ ligands caused a significant dose-dependent inhibition of cancer cell growth [100]. PPARγ can be activated by both endogenous ligands, such as fatty acids and their derivatives, including the eicosanoid, 15deoxy-Δ12(14-prostaglandin J2, 15d-PGJ2) and synthetic ligands, such as 4-hydroxyphenylretinamide and the thiazolidinedione class of antidiabetic agents [101]. There have been many studies focused on the thiazolidinedione family of therapeutics, including rosiglitazone and pioglitazone, which are high-affinity agonists of the nuclear receptor PPARγ [102]. Several inflammatory pathways, such as NF-κB, PGE2 and MKP-1, were reported to be related to PPARγ-independent anti-tumor activities of rosiglitazone and regulation of other apoptosis-related cell factors [103]. By increasing the expression of MKP-1, rosiglitazone suppressed tumor proliferation and metastasis by reducing the activity of metalloproteinase-2 (MMP-2) and CXCR4 activities [103]. Another study revealed that rosiglitazone could decrease the incidence rate of OSCC by lowering an oral carcinoma invasion score. However, the chemopreventive effectiveness was greatly reduced if the rosiglitazone was delayed when used as an adjunctive therapeutic [104]. Pioglitazone was also reported to possess anti-tumor activity by reducing the activation of MAPK in various cancers [93,105–106]. In an OSCC study, pioglitazone reduced the incidence OSSC rate cancer, but there was no significant effect on cancer invasion [104]. These data support the concept that PPARγ agonists, through induction of MKP-1, may potentially have benefit in OSCC management.

DUSP4 was identified to be responsible in mutagen sensitivity [127]. Downregulation of DUSP5 as potential mechanisms leading to cetuximab resistance in OSCC [128] Downregulation of DUSP6 as potential mechanisms leading to cetuximab resistance in OSCC [128]

DUSP2 methylation positivity was more frequent among patients with small tumor size [124]. DUSP4 activation may contribute to ERK inactivation [125]. Unknown

DUSP1 protein increases the cell death elicited by hyperthermia death and autophagy [122–123]

DUSP1 mRNA increase in quiescent OSCC cells suggesting DUSP1 could play a role in the cell growthstate specific radiation response [95]. Increase of MKP-1 activity correlates with decrease of HNC radiosensitivity [94]. DUSP2 expression is a determinant of cellular sensitivity to some cytotoxic agents, including cisplatin [124]. p38, IL-1β Inhibit

Down-regulation in OSCC enhance susceptibility to carcinogen-induced oral cancer, enhanced tumorassociated inflammation, increased Il1β expression [51]

Molecular Targets Carcinogenesis Expression MKP Family Member

Table 2 Summary of MKPs in Oral Squamous Cell Carcinoma Tumor Biology.

Survival and Clinical Outcomes

Impact on Oncological Therapies

Biological Function in OSCC

Z. Li, et al.

Summary The MAPKs family play a crucial role in the development of human OSCC. p38 MAPK, negatively controlled by MKP-1, can promote in a wide range of cellular processes related to cancer progression, and play a crucial role innate and adaptive immune responses. Based upon the current literature to date, the concept that p38 MAPK is increased while the expression of MKP-1 is reduced by epigenetic mechanisms appears to be reasonable. These cancer cell intrinsic alterations lead to a change in macrophage polarization with the OSCC TME favoring M2 polarized TAMs (see Figure 3). Understanding how p38/MKP-1 signaling pathways regulates OSSC processes may be vitally important to develop more effective therapies. This review highlights the potential to target 6

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Fig. 3. The p38/MKP-1 axis in oral cancer progression. In the oral cavity, oral epithelium is bathed in an environment that initiate oral cancer through multiple mechanisms, including genetic/genomic mutations, epigenetic modifications, and chronic inflammation. Once cancer has been initiated DUSP1 gene promoted is hypermethylated resulting in gene silencing and reduced MKP-1 expression in oral squamous cell carcinoma (OSCC) epithelium. This reduction in MKP-1 expression results in increased levels of activated p38 and ERK MAPKs that alter tumor associated macrophage (TAM) polarization towards an M2 phenotype which can facilitate OSCC progression through multiple mechanisms (see text for details).

the p38/MKP-1 axis in OSCC treatment and management. By both increasing the chemosensitivity of tumors to traditional chemotherapeutics as well as potentially reprograming TAMs in the TME to promote more tumoricidal activity, these agents could be used in both conventional and potentially as a novel neoadjuvant for immunotherapeutic approaches to manage oral cancer. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Acknowledgements The authors would like to acknowledge support from the National Institutes of Health Grants R01DE028258, R21DE027017, and K18DE029526 to KLK and the China Medical University that supported ZL and FL as Visiting Scholars. 7

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