H19 lncRNA: Roles in tumorigenesis

Biomedicine & Pharmacotherapy 123 (2020) 109774

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Review

H19 lncRNA: Roles in tumorigenesis a

b

c,

Soudeh Ghafouri-Fard , Mohammadhosein Esmaeili , Mohammad Taheri * a b c

T

Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

ARTICLE INFO

ABSTRACT

Keywords: H19 lncRNA Cancer Biomarker

H19 is a long non-coding RNA [lncRNA] which was firstly described as an oncofetal transcript. The imprinted gene is normally expressed from the maternal allele. However, this pattern of imprinting is dysregulated in several cancers leading to aberrant up-regulation of H19 in malignant tissues. Several studies have utilized this aberrant expression pattern to find specific biomarkers for detection of cancer in tumoral tissues or peripheral blood. Moreover, single nucleotide polymorphisms within H19 have been associated with risk of oral squamous cell carcinoma, hepatocellular carcinoma, breast cancer, bladder cancer, gastric cancer and colorectal cancer. Taken together, H19 is regarded as a biomarker for cancer and a putative therapeutic target in these human disorders.

1. Introduction Being nominated by Pachnis et al., H19 has been identified as an ample fetal transcript in mice in 1984 [1]. Alternatively, it has been designated as Adult Skeletal Muscle gene, based on its expression in skeletal muscles of rats [2]. Subsequent investigations revealed its expression in tumors originating from tissues which show expression of this gene in the fetal period. In addition, expression of H19 in both conditions was associated with level of tissue differentiation [3]. This imprinted gene is located on chromosome 11p15.5 and is expressed exclusively from the maternal allele. Experiments in the testicular germ cell tumors which have the patterns of differentiation of the embryo, validates disconnection between expression levels and monoallelic versus biallelic patterns of expression. Moreover, assessment of expression pattern of H19 in the complete hydatidiform mole has shown relaxation of imprinting [4]. This oncofetal RNA has been designated as a long non-coding RNA [lncRNA] which participates in the pathogenesis of several human cancers [5–7]. H19 expression is increased following hypoxic stress via the p53/HIF1-α pathway. Besides, H19 silencing inhibits hypoxia-related cancer cell proliferation [8]. Numerous functional studies have assessed relevant functions of this lncRNA in the pathogenesis of human cancers among them are those depicted in Fig. 1. In addition to its role in the carcinogenic process, H19 is involved in the pathogenesis of some other human disorders H19 Beckwith-

⁎

Wiedemann Syndrome [14] and male infertility [15]. In the present review, we summarize the most recent data on expression of H19 in human cancers, the diagnostic and prognostic value of this lncRNA and associations between the single nucleotide polymorphisms [SNPs] within this lncRNA and risk of cancer. 2. H19 imprinting Previous studies have shown reciprocal imprint for mouse insulinlike growth factor 2 [Igf2] and H19 genes which are located near each other on mouse chromosome 7. These studies have revealed the presence of two regulatory regions namely a differentially methylated region [DMR] upstream of H19 and a number of tissue-specific enhancers downstream of H19. While these enhancers induce expression of Igf2 from the paternal allele, they activate exclusive expression of H19 from the maternal chromosome [16]. This pattern of expression has been detected in normal human gestations, but disrupted in uniparental gestations. While neither H19 nor IGF2 is expressed from the maternal genome of ovarian teratomas, both genes are expressed from the paternal allele in androgenetic complete hydatidiform moles [17]. Abnormal imprinting pattern of H19 has been also detected in semen samples from infertile males in correlation with hypermethylation of methylenetetrahydrofolate reductase gene promoter [15]. Cui et al. have demonstrated an alternative mechanism for aberrant methylation pattern of H19 in colorectal cancer. They have shown that the pre-

Corresponding author. E-mail address: [email protected] (M. Taheri).

https://doi.org/10.1016/j.biopha.2019.109774 Received 28 October 2019; Received in revised form 23 November 2019; Accepted 4 December 2019 0753-3322/ © 2019 The Author(s). Published by Elsevier Masson SAS. This is an open access article under the CC BY license (http://creativecommons.org/licenses/BY/4.0/).

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S. Ghafouri-Fard, et al.

viously acknowledged method of loss of imprinting [LOI] i.e. hypermethylation of the DMR upstream of the H19 gene does not explain LOI in colorectal cancers as they demonstrated hypomethylation of this region in both cancerous tissues and normal mucosa of these patients. Based on these observations, they proposed an alternative model for LOI which implicates a transcriptional repressor functioning on the normally imprinted maternal allele of IGF2 [18].

c-Myc [19]. Assessment of functional networks between lncRNAs, transcription factors and miRNAs has revealed H19 as a putative network hub which is functional in several cancers. The node belonging to H19 had a large degree and was associated with several types of cancer implying its role in pan-cancer development [20]. Ning et al. have depicted the lncRNA-mediated feed-forward loop motifs [L-FFL] and reported that some dysregulated L-FFL and competing endogenous RNA [ceRNA] motifs have common miRNAs and lncRNAs in several kinds of cancers. One L-FFL which includes H19, the transcription factor MYC and miR-29c, and a ceRNA motif containing the mRNA COL3A1, H19 and miR-29c, were both dysregulated in breast cancer. Consequently, the L-FFL and ceRNA motifs may have complicated regulatory functions and interactions in cancer [20].

3. H19 regulation and regulatory loops H19 expression is regulated by several factors among them are wellknown oncogenes. Through chromatin immunoprecipitation assay, Zhang et al. have shown that expression of this lncRNA is regulated by

Fig. 1. H19 exerts its oncogenic roles via different mechanisms which might depend on the type of cancer. [A] In gastric cancer cells, increased level of H19 has been associated with over-expression of miR-675. Up-regulation of these two genes enhanced cell proliferation and suppressed cell apoptosis, while their silencing had the opposite effects. H19/miR-675 axis repressed expression of Fas-associated protein with death domain [FADD] leading to inhibition of the caspase cleavage cascades [9]. [B] In cholangiocarcinoma, H19 regulates cell migration and invasion through modulating expression of IL-6 and CXCR4. This effect of H19 is exerted via sponging let-7a/let-7b [10]. [C] In colorectal cancer cells, H19 enhances migration and invasion of cancer cells through sponging miR-138 and subsequent enhancing HMGA1expression [11]. HMGA1 inhibit expression of IGFBP2 and Grb14 which are inhibitors of IGF2 and IGF1R proteins, respectively [12]. [D] In multiple myeloma, H19 over-expression induces IƙB phosphorylation and transport of P50/P65 heterodimer to the nucleus leading to increased expression of selected genes from NF-ƙB signaling pathway and tumorigenesis [13].

2

3

miR-29b-3p/PGRN/Wnt

EMT pathway miR-148a-3p, DNMT1 NF-κB pathway

Esophageal cancer Laryngeal squamous cell carcinoma Multiple myeloma

AMPK and MMP9 IL-6 and CXCR4 EMT pathway – miR-194-5p/ EMT pathway ID2 p53 activation c-Myc miR-17/ STAT3 – miR-138 miR-194-5p, SIRT1 – ZEB1 and ZEB2 / E-cadherin NF-κB pathway miR-630 miR-17-5p IRS-1 / PI3K-AKT pathway miR-106a-5p/E2F3 axis NF-κB and PI3K/Akt EMT pathway HMGA2-mediated EMT E2F-1

Colorectal cancer

Pancreatic ductal adenocarcinoma

Melanoma

Nasopharyngeal carcinoma Thyroid cancer

Papillary thyroid carcinoma Osteosarcoma

Chronic myeloid leukemia Non-small cell lung cancer Cervical cancer Colon cancer

Acute myeloid leukemia Colorectal adenocarcinoma Bladder cancer

Cholangiocarcinoma

Gastric cancer

Breast cancer

Tongue squamous cell carcinoma

Gallbladder cancer

Glioma tumor Ovarian cancer

miRNA let-7 miR-152 Akt and ERK – H19/SAHH/DNMT3B axis – FADD / caspase 8 and caspase 3 pathways ZEB1

– miR-675 EZH2 HOXA10 EMT pathway miR-675 H1.3 – – miR-194-5p/AKT2 axis EZH2/ β-Catenin-GSK3β-EMT let-7a/ EMT pathway

Glioblastoma

Endometrial carcinoma

Targets/ Regulators and Signaling Pathways

Cancer type

TE-1, TE-10, Eca-1, Eca-109, KYSE1170 Hep-2 OPM-2, U266, KM3, XG1, JJN3, RPMI, U1996, H929, MM1S

AGS, SGC7901 QBC939, SK-cha-1, RBE, HEK293T RBE, HCCC-9810, QBC939, Huh-28, HuCCT1, KMBC, CCLP-1, HIBEC HL60 HCT116, HT-29, RKO, SW280, Lovo, CCD-18Co RT4, RT112, DSH1, 253 J, TCCSUP, T24, KU7 RT4, HT-1376, 5637, 253 J, TCCSUP, T24, J82 K562, Jurkat A549, H1299, BES-2B Primary fibroblasts, HeLa, SiHa, MS751, C33A, Ect1/E6E7 CCD-18Co, HIEC, Int-407, SW480, HT-29, colon26, HCT-8, RKO HCT8, HCT8Fu Nthyori 3-1, K1, B-CPAP, IHH-4 MG63 MG-63, U2OS, SAOS-2, hFOB NP69, CNE2, CNE1, HONE1 TPC-1, NIM, BCPAP, Nthy-ori3-1 SW579, TPC-1 A375, SK-MEL-1, SK-MEL-5 C32, SK-MEL-28, CCD-1059Sk CHL-1, UACC904, A-375, 1205Lu PANC-1, SW1990, AsPC-1, BxPC-3, CFPAC-1 COLO357, CAPAN-1, MIAPaCa-2, AsPC-1, BxPC-3, PANC-1, T3M4, SW 1990, hTERT-HPNE HCT116, HT-29, SW620, SW480, NCM460

MKN45, 7901 cells, GES-1

MDA-MB-231, SK-BR-3, MCF-7 MCF-7, MDA-MB-231, Hs 578Bst MCF-7 and T47D, MDA-MB-231 MCF-7, MDA-MB-231 MCF7, MCF7/ TAMR [tamoxifen-resistant] SGC7901, BGC823, MGC803, AGS, MKN45,GES1 SGC-7901, SGC-7901/DDP, GES-1

U87, U373 U87, U251 A172, LN229, U87MG, LN18, T98G HEC1-A, HEC1-B, AN3CA, Ishikawa HEC-1-B U251, U87, NHA OVCAR-3 SKOV3, OV90, TOV112D, ES2 NOZ, GBC-SD, SGC-996, EH-GB1 GBC-SD, EH-GB1, NOZ Cal27, SCC9, SCC15, SCC25, Tca8113, UM1 CAL27, SCC9, SCC15, SCC25, FaDu,

Assessed cell lines

[66] [67] [13]

[65]

[50] [10] [51] [52] [53] [54] [55] [56] [5] [57] [11] [31] [21] [58] [59] [60] [61] [22] [62] [63] [64] [7] [6]

[49]

[44] [45] [46] [47] [30] [48] [11]

[32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43]

Reference

(continued on next page)

ΔH19: ↓snail, ↓vimentin, ↑E-cadherin, ↓proliferation, ↓ metastasis ΔH19: ↓proliferation, ↓invasion ΔH19: ↓proliferation, ↓invasion, ↓migration ΔH19: ↓cell growth, ↓cytokine secretion

ΔH19: ↓proliferation, ↓DICER and DROSHA [RNA processing enzymes] ΔH19: ↓invasion ΔH19: ↓migration, ↓invasion ΔH19: ↑apoptosis, ↓cell proliferation, ↓migration, ↓invasion ΔH19: ↑apoptosis, ↓proliferation ΔH19: ↑E-cadherin, ↓N-cadherin, ↓Vimentin ΔH19: ↓proliferation, ↓ID2 expression ΔH19: ↓proliferation ΔH19: ↑apoptosis, ↓tumor growth ΔH19: ↓proliferation, ↓migration, ↓invasion ΔH19: ↓proliferation ΔH19: ↓migration, ↓invasion ΔH19: ↓autophagy ↑H19: ↓proliferation, ↓migration ΔH19: ↓migration, ↓invasion ΔH19: ↓migration, ↓invasion ΔH19: ↓invasion ΔH19: ↓cell viability, ↓invasion, ↑growth arrest ΔH19: ↑cell viability, ↑invasion, ↑migration ΔH19: ↓proliferation ΔH19: ↓proliferation, ↓invasion, ↓migration ΔH19: ↓migration, ↓invasion, ↓growth, ↑apoptosis ΔH19: ↓migration, ↓invasion ΔH19: ↓proliferation, ↓viability, ↓growth

↑H19: ↑angiogenesis, ↑invasion ΔH19: ↓invasion ΔH19: ↓viability, ↓invasion, ↓migration ΔH19: ↓cell viability ΔH19: ↑E-cadherin, ↓snail, ↓migration, ↓invasion ΔH19: ↓proliferation ΔH19: ↓growth rate ΔH19: ↑apoptosis, ↓cell growth ΔH19: ↑E-cadherin, ↓Twist1, ↓Vimentin ΔH19: ↓invasion, G0/G1 arrest, ΔH19: ↑apoptosis, ↓cell growth, ↓invasion ΔH19: ↑E-cadherin, ↓Vimentin, ↓N-cadherin, ↓twist, ↓zeb1, ↓ snail1 ΔH19: ↓clonogenicity, ↓migration and ↓sphere-forming ability ΔH19: ↓proliferation, ↓invasion ↑H19: ↑migration, ↑proliferation ΔH19: ↓cell survival, ↓estrogen-induced cell growth ΔH19: ↓autophagy ΔH19: ↓migration, ↓invasion ΔH19: ↑apoptosis, ↓proliferation

Function

Table 1 Summary of studies which assessed expression and function of H19 in cell lines [Δ: knock down or deletion, EMT: epithelial-mesenchymal transition].

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Calu‑3, NCI‑H1975, A549 and NCI‑H23 A549 H19/miR‑29b‑3p/STAT3 signaling miR-484, ROCK2

[25] [24]

Hep G2, HCCLM3 PI3K, Akt and mTOR Hepatocellular carcinoma

[29]

[68]

ΔH19: ↓proliferation, ↓invasion, ↓migration, ↓vimentin, ↑Ecadherin ΔH19: ↓hypoxia/reoxigenation-induced apoptosis, ↓cell damage ΔH19: ↓viability, ↓EMT process ΔH19: ↓cell viability, migration, and invasion, ↑apoptosis ↑H19: ↑cell migration, invasion, and EMT process. – Esophageal squamous cell carcinoma

Het-1A, EC109, EC9706, KYSE150, KYSE450

Reference Function

Several studies have reported up-regulation of H19 in cancer cell lines and samples obtained from patients. Moreover, functional studies have verified the oncogenic effects of H19. Following sections demonstrate the role of H19 in the carcinogenic process based on the results of cell line studies, animal studies and expression analyses in human samples, respectively. 5. Cell line studies Totally, cell line studies have shown up-regulation of H19 in cancer cell lines compared with non-cancerous cell lines of the same origins. Moreover, such up-regulation was correlated with invasive behavior of cancer cells. Several knock-down studies have verified decrease in viability, invasion and migration potentials of cancer cell lines after H19 silencing. Contrary to the bulk of evidence, a single study has reported lower expression of H19 in K1 and IHH4 papillary thyroid cells compared with a normal thyroid follicular epithelial cell line [Nthy-ori 3-1] [21]. Another group has demonstrated that H19 suppresses cell viability, migration, and invasion in SW579 and TPC-1 thyroid cancer cells [22]. On the contrary, a recent study has shown oncogenic effects of in HL60 thyroid cancer cells which are mediated through regulating the PI3K/AKT pathway [23]. Although several target genes have been identified for H19, the most affected pathway or process by H19 is possibly the epithelialmesenchymal transition [EMT] process. In lung cancer cells, H19 silencing has reduced expression of proteins in JNK pathway. In addition, ROCK2 has been identified as the main downstream target of H19 in these cells. The effect of H19 in enhancement of EMT process in lung cancer is mainly exerted through down-regulation of miR-484 [24]. Another study in lung cancer has miR-29b-3p and STAT3 as critical regulators of EMT which are influenced by H19 [25]. A similar process has been identified in bladder cancer, as H19 regulates this process through sponging miR-29b-3p in these cells [26]. A number of studies have demonstrated the role of H19 in conferring resistance to conventional therapeutic options. For instance, Luo et al. reported the effects of H19 silencing on suppression of cells proliferation, migration and stemness in the radioresistant esophageal squamous cell carcinoma cells. They also demonstrated that H19 silencing decreases expression of WNT1 via upregulating miR-22-3p expression [27]. In breast cancer cells, H19 silencing has enhanced tamoxifen sensitivity in tamoxifenresistant breast cancer cells possibly through inhibition of Wnt pathway and EMT process [28]. H19 also has a fundamental role in regulation of autophagy in human cancers. Cui et al. have shown that H19 stimulates hypoxia/reoxygenation [h/R] injury through activation of autophagy in the hepatoma carcinoma cells. Its silencing has diminished the autophagic vesicles [AVs] and the expression of Beclin-1 and the ration of LC3-II/LC3-I, and increased cell viability. Functional studies have shown that H19 is a stimulator of h/R injury which up-regulates autophagy through induction of PI3K-Akt-mTOR pathway in the hepatocellular carcinoma cells [29]. In breast cancer cells, the role of H19 in induction of autophagy through the H19/SAHH/DNMT3B axis might participate in generation of tamoxifen resistance [30]. Besides, in colorectal cancer cells, H19 stimulates autophagy to confer resistance to 5-fluorouracil [31]. Table 1 summarizes the results of studies which assessed functional roles of H19 in cancer cell lines. 6. Animal studies Consistent with the results of cell line studies, animal studies have shown that over-expression of H19 in cancer cells has increased tumorigenic potential of these cells, while its silencing has decreased

Lung cancer

Assessed cell lines Targets/ Regulators and Signaling Pathways Cancer type

Table 1 (continued)

4. Expression of H19 in cancers

4

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Table 2 Summary of studies which assessed function of H19 in animal models [Δ: knock down or deletion]. Cancer type

Animal models

Functions

Reference

Glioblastoma Gallbladder cancer Tongue squamous cell carcinoma Breast cancer

Female BALB/c athymic mice Male nude mice BALB/c-nu mice TA1 and TA2 mouse strains Nude mice Specific pathogen-free athymic nude mice [male, age: six to eight weeks] Nude mice female nude mice male athymic BALB/c mice

↑ H19: ↑tumor formation, ↑proliferation, ↑angiogenesis ΔH19: ↓tumor growth, ↑E-cadherin, ↓Vimentin ΔH19: ↓metastasis, ↓tumor weight, ↓tumor volume ΔH19: ↓metastasis ΔH19: ↓autophagy, ↓tamoxifen resistance ΔH19: ↓tumor growth, ↓tumor volume

[32] [40] [42] [45] [30] [11]

ΔH19: ↓tumor weight ΔH19: ↓tumor growth ΔH19: ↓cell proliferation

[62] [64] [19]

Colon cancer Melanoma Non-small cell lung cancer

tumor growth. In a xenograft model of glioblastoma, stable overexpression of this lncRNA has enhanced tumor growth [32]. The results of knock-down studies consistently showed oncogenic roles of H19 in gall bladder cancer, squamous cell carcinoma of tongue, melanoma and cancers of breast, colon and lung. Table 2 summarizes the results of studies in animal models.

gastric cancer patients from controls with diagnostic power of 0.838. Moreover, it facilitated differentiation of early stage gastric cancer from controls with accuracy of 0.877 [68]. Hashad et al. have reported that combination of arcinoembryonic antigen [CEA] and H19 levels has a diagnostic power of 0.80 in gastric cancer [77]. The best diagnostic power has been reported in papillary thyroid cancer where H19 has been shown to be down-regulated. In this kind of cancer, H19 levels could differentiate cancerous and non-cancerous tissues and could predict lymph node metatstais [21]. Table 4 summarizes the results of human studies which assessed diagnostic power of H19 in different cancers.

7. Human studies Over-expression of H19 has been reported in cancers originated from different sites. However, the results of expression studies in thyroid cancer are not consistent with other types of cancers. A single study has shown down-regulation of H19 in papillary thyroid carcinoma and its association with lymph node metastasis [21]. Most studies have used adjacent non-cancerous tissues of the same patients as controls [summarized in Table 3]. Most of listed studies have shown significant correlation between over-expression of H19 and poor survival rate of cancer patients. However, a single study in gastric cancer patients showed no prognostic value for plasma H19 levels through the Kaplan-Meier method [69]. Another study in acute myeloid leukemia [AML] showed the prognostic role of this lncRNA in non-APL-AML patients but not in whole-cohort of AML or cytogenetically normal-AML patients [52].

9. Association between H19 SNPs and risk of cancer Some H19 SNPs has been associated with risk of human malignancies. The most assessed SNP is rs217727. This SNP has not influenced the H19 mRNA level in gastric cancer patients or controls [80]. However, the A/A genotype of this SNP has conferred risk of both squamous cell carcinoma and adenocarcinoma of in Chinese population [81]. Another study in Chinese population revealed no significant association between rs3741219 and rs217727 SNPs and risk of breast cancer in univariate analysis. Yet, CT + TT genotypes of rs217727 were shown to decrease risk of breast cancer among women who had more than two pregnancies. CT genotype of this SNP was associated with positivity for estrogen receptor and HER-2 [82]. A previous study has assessed association between five tag SNPs of H19 and risk of bladder cancer. Authors have shown that the rs2839698 TC genotype and rs2107425 CT genotype decrease risk of bladder cancer. The rs2839698 TC genotype was remarkably associated with a decreased risk of nonmuscle-invasive bladder cancer [83]. The rs2107425 was significantly associated with shorter metastasis-free survival of breast cancer patients. However, this SNP did not affect expression of H19 in the assessed patients [84]. Furthermore, the CT + TT genotypes of the rs217727 and the CT + TT genotypes of the rs2839698 were associated with higher risk of gastric cancer [80]. Besides, the CT and TT genotypes in rs2839698 were associated with elevated serum levels of H19 [80]. Table 5 shows the results of association studies which assessed contribution of H19 SNPs in risk of different cancers.

8. Diagnostic value of H19 in human cancers Assessment of the diagnostic value of H19 in differentiation between cancer and non-cancerous conditions has been the subject of a few studies. Gastric cancer has been among the mostly assessed cancers in this regard. Yörüker et al. have reported higher amounts of circulating H19 in gastric cancer patients compared with cancer-free persons. Notably, there was an inverse tumor size and level of H19 expression in the circulation. Yet, plasma levels of H19 dropped considerably upon surgical removal of tumors [69]. Chen et al. have reported that diagnostic power of H19 in differentiation between tumoral and adjacent non-tumoral tissues was 0.69. Most notably, they reported higher expression of H19 in gastric juice of cancer patients compared with controls [48]. Zhou et al. assessed diagnostic value of plasma level of H19 in gastric cancer. H19 levels could differentiate

5

6

Laryngeal squamous cell carcinoma Multiple myeloma

Colorectal cancer

Osteosarcoma

82 matched cancerous and noncancerous tissues 30 patients

30 primary malignant melanoma tissues and adjacent normal tissues 40 cancer and adjacent healthy tissues 185 paired of cancer tissue samples and non-tumor normal tissues 83 cancer patients

Melanoma High levels of H19 expression was correlated with low OS. OS rate of patients with under-expressed H19 performed far better than that of ones with over-expressed H19. 4-years DFS and median survival time was lower for patients with high H19 levels. Patients with high H19 expression had poorer OS. DFS was lower for patients with high H19 levels.

High H19 expression was associated with poor survival.

110 cancer tissues and paratumor tissues

62 tumor tissues and 19 histologically confirmed adjacent normal tissues

High H19 expression was significantly associated with poor recurrent free survival. High levels of H19 expression was associated with worse OS and shortened DFS.

214 paired of cancer and adjacent normal tissues

Colorectal adenocarcinoma

Head and neck squamous cell carcinoma

–

161 AML patients and 36 healthy donors

180 breast cancer samples

20 breast cancerous tissues and adjacent normal tissues

Acute myeloid leukemia [AML]

Breast cancer

High level of H19 was associated with poor OS. High H19 level was a strong indicator for an inferior overall survival in breast cancer patient samples. H19 expression was associated with shorter survival. H19 overexpression was associated with shorter OS.

123tumor tissues and 50 adjacent non-tumor tissues 40 cancer patients and 42 normal controls 128 cancer patients

Tongue squamous cell carcinoma Gastric cancer

80 primary cancer patients

24 tumor and adjacent tissues

Gallbladder cancer

High H19 expression was significantly associated with poor progression-free survival rate. High H19 expression was correlated with poor OS. High H19 expression was correlated with shorter lifespan. There was no difference in survival rate between the groups. High H19 expression was associated with higher recurrence rate and shorter OS. High H19 expression was correlated with poor OS.

30 tissue specimens

Glioblastoma

Kaplan-Meier analysis

74 paired cancer and noncancerous tissues

Numbers of clinical samples

Cancer type

H19 expression was an independent prognostic indicator of DFS.

can be used as an independent predictor of the OS of patients with GC – –

H19 expression, TNM stage and distant metastasis were associated with DFS. Invasion depth, regional lymph nodes, H19 expression, TNM stage and distant metastasis were related to OS. Number of lymph nodes, metastasis, advanced TNM staging and H19 expression were significant prognostic factors. Histological grade, lymph node metastasis, TNM stage and H19 expression were prognostic factor. – –

– –

Survival rate of patients with higher levels of H19 was lower than patients with lower expression.

[13]

[67]

[74]

[65]

[59]

[62]

[73]

[31]

[53]

[52]

[72]

[44]

[71]

[70]

[48]

[69]

[42]

[40]

[32]

Reference

(continued on next page)

H19 expression, TNM stage and tumor differentiation were strongly associated with DFS.

– –

Distant metastasis and high expression level of H19 were associated with mortality of patients. –

–

H19 overexpression together with higher miR-675 and lymph node metastases were independent prognostic factors for poor DFS.

High H19 expression might act as an independent prognostic biomarker for poor OS in non-APL-AML patients but not whole-cohort of AML or cytogenetically normal-AML patients Higher H19 expression, lower miR-194-5p expression, lower grade of differentiation, late stage, lymph node metastasis and distal metastasis played as the independent determinants for poor prognosis of patients. –

Expression level of H19 was positively associated with distant metastasis but not with gender and age. –

Overexpression of miR-675 was significantly correlated with higher expression of H19 and lymph node metastases, but not with sex, age and primary tumor location. –

–

–

–

–

–

–

–

–

–

Multivariate cox regression

–

–

–

Univariate cox regression

Table 3 Summary of studies reported up-regulation of H19 in clinical samples [DFS: disease free survival, OS: overall survival].

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[76]

[19]

TNM stage and H19 expression were identified as prognostic factors. –

Can be used as an independent predictor for overall survival in patients. –

H19 has been described as an imprinted gene for about three decades. Previous studies mostly evaluated the effects of this lncRNA in human malformation syndromes such as Beckwith-Wiedemann Syndrome and uniparental gestations. Soon after, researchers have described this transcript as an oncofetal transcript to show its contribution in the carcinogenic process. Now, this transcript is known as an oncogenic lncRNA which participated in the pathogenesis of several human cancers through different mechanisms among them is the ceRNA role. An exception in this regard is thyroid cancer, in which the results of studies regarding the role of H19 [oncogene versus tumor suppressor] are not consistent. The most important function of H19 is the tumorigenesis is possibly its effects in enhancing EMT process and metastasis. Several EMT modulators have been shown to induce H19/ miR-675 expression. Consequently, the H19 /miR-675 axis has been described as a shared feature of EMT inducers [94]. Mechanistically, H19 can exert its oncogenic effects through activation of autophagy, inhibition of apoptosis and enhancement of EMT which in turn increases invasive properties of cancer cells. Moreover, it can increase the number of cells in the S phase of cell cycle. Future studies are needed to investigate whether all cancer types exhibit all of these features or there is an individualized oncogenic mechanism for each type of cancer. A distinct point about this lncRNA is the well-appreciated role of epigenetic factors in the regulation of its expression. The presence of a DMR upstream of the H19 potentiates design of targeted epigenetic therapies for regulation of expression of this lncRNA. Diagnostic value of this lncRNA for differentiation between cancer patients and healthy status was acceptable. Notably, assessment of expression level of H19 in plasma or other body fluids such as gastric juice has provided promising results to be applied as non-invasive methods for cancer diagnosis. Moreover, plasma levels of H19 might be combined with conventional serum biomarkers to yield higher diagnostic power. Knock-down studies have verified feasibility and effectiveness of H19-targeted therapies in xenograft models of several cancers. These studies have provided the final steps for translation of basic studies on “the oncogenic role of H19″ into the clinics. Availability of non-invasive methods for screening of H19 levels further support the feasibility of these approaches. in vivo studies have indicated the efficacy of H19 silencing in decreasing tumor burden and chemoresistance in gall bladder cancer, squamous cell carcinoma of tongue, melanoma and cancers of breast, colon and lung. The functional roles of H19 in modulation of several aspects of malignant behavior imply the efficacy of H19-targetted therapies in human subjects as well. However, based on unavailability of sufficient pre-clinical evidences in this regard, such treatment strategy has not been tested in clinical trials yet. Several SNPs near H19 has been associated with risk of human cancers. However, the effects of these SNPs on expression or function of H19 is largely unexplored. So, future studies are necessary to evaluate the effects of these SNPs and related haplotypes on expression of H19 in different tissues to clarify the mechanism for their contribution in cancer risk. Moreover, the functional effects of SNPs on response of patients to chemotherapy or radiotherapy have not been examined yet. Taken together, the fundamental role of H19 in EMT and metastatic potential of cancer cells has potentiated this lncRNA as a therapeutic target in cancer.

200 patients

56 tumoral tissues and corresponding adjacent nontumor tissues 70 patients Cholangiocarcinoma

Non-small cell lung cancer

92 patients Clear cell renal carcinoma

H19 overexpression was associated with poor prognosis. High level of H19 was associated with poor OS.

[51] – –

Numbers of clinical samples

High level of H19 was associated with shorter OS. 5-years OS rates and median survival was low for H19 high expression group.

–

–

[75]

10. Discussion

Cancer type

Table 3 (continued)

Kaplan-Meier analysis

Univariate cox regression

Multivariate cox regression

Reference

S. Ghafouri-Fard, et al.

Declaration of Competing Interest The authors declare they have no conflict of interest.

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Table 4 Diagnostic value of H19 in cancers [PTC: papillary thyroid carcinoma, AML: Acute myeloid leukemia, MM: multiple myeloma]. Cancer Type

Numbers of clinical samples

Distinguish between

Area Under Curve

Sensitivity

Specificity

Reference

Gastric cancer

40 cancer patients and 42 normal controls 128 paired tumoral tissues and adjacent non-cancerous tissues 32 cancer patients and 30 normal controls 90 cancer patients and 90 healthy controls 161 AML patients and 36 healthy donors 75 paired of tumor tissues and para-cancerous thyroid tissues 80 patients and 67 healthy controls 24 paired of BC tissues and 20 paired of BC plasma

Cancer patients and controls Tumor and non-tumor tissues

64.3% 0.697

87.2 62.0

38.1 74.0

[69] [48]

Cancer and control samples Patients and normal controls Patients and controls PTC and noncancerous diseases

72.4% 0.838 0.655 0.894

68.75 82.9 49.1 88.0

56.67 72.9 80.6 76.0

[77] [68] [52] [21]

MM and normal samples Tumor and normal samples

0.88 0.81

77.5 56.7

88.1 86.7

[78] [79]

Acute myeloid leukemia Papillary thyroid carcinoma Multiple myeloma Breast cancer

Table 5 H19 polymorphisms and their association with cancer risk. Cancer type

Number of cases

H19 variant associated with Cancer risk

Reference

Oral squamous cell carcinoma

362 444 472 193 230

rs217727 rs217727 rs2839701 rs2839698 rs217727 rs3741219 rs217727 rs2839698 rs3741216 rs2839698 rs217727 rs217727 rs217727 rs217727 rs2839698 rs2839698

[85] [86] [87] [88] [89]

Hepatocellular cancer Osteosarcoma Breast cancer

patients and 741 healthy controls patients and 984 healthy controls patients and 472 matched controls patients and 393 controls cases and 240 controls

111 patients and 130 age-matched controls Bladder cancer Gastric cancer Colorectal cancer

464 patients and 467 controls 1049 cancer cases and 1399 controls 500 patients and 500 control 1147 patients and 1203 controls

Acknowledgment

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