miR-202 as a Novel Gastrointestinal Tract Tumor Suppressor: History
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Contributor:
Emad A. Ahmed
,
Peramaiyan Rajendran
,
Harry Scherthan

Numerous clinical studies have addressed the role of miR-202 in gastrointestinal tract tumors (GIT), including oral, esophageal, gastric, pancreatic, hepatocellular, and colorectal cancers, and documented a lower expression of miR-202 in tumor tissues and a tumor suppressive function of miR-202 overexpression on GIT cancer progression. In oral cancer cell lines, overexpression of miR-202 downregulated the protein expression level of the transcription factor Sp1, which, in turn, reduced cancer cell migration and invasion. Inhibition of miR-202, however, markedly enhanced oral cancer progression, indicating a suppressor function of miR-202 in this tumor type. A tumor suppressive function for miR-202 has also been proposed by Meng and colleagues in esophageal squamous cell carcinoma.

  • microRNA-202
  • cancer
  • tumor suppressor
  • lncRNA
  • diagnostic biomarkers

1. Downregulation of miR-202 in Gastric Cancer Is a Potential Biomarker for Tumor Progression

Worldwide, gastric cancer (GC) is one of the most frequent causes of cancer mortality [1][2]. To date, three clinical studies investigated the role of miR-202 in GC and the obtained conclusive results revealed that miR-202 is downregulated in tumor tissues relative to the adjacent healthy tissues [3][4][5]. Interestingly, miR-202 expression levels were found to vary with the tumor size and patient age [3]. In addition, overexpression of miR-202-3p in GC cell lines caused a marked suppression of cell proliferation and induced apoptosis under in vitro condition and in xylographed nude mice. This tumor suppression activity occurred via direct targeting the transcription factor Gli1 and inhibition of the expression of the Gli1 target genes γ-catenin and BCL-2 [3]. Similarly, miR-202 was reported to be targeted by the LncRNA MALAT1, whose knockdown significantly reduced the expression of Gli2 via negative regulation of miR-202. In agreement, a negative correlation has recently been observed between miR-202-3p and MALAT1 expression, where upregulation of the latter increased the level of the splicing factor SRSF1 via targeting miR-202-3, thus activating the mTOR pathway to enhance GC migration and epithelial-mesenchymal transition (EMT) [5]. On the other hand, miR-202-3p was the most extraordinarily upregulated miRNA in type 1 gastric neuroendocrine neoplasm [6]. In all, downregulation of miR-202 in GC (Table 1) is a potential biomarker indicative of tumor progression.

2. The Role of miR-202 in Pancreatic Cancer and Hepatocellular Carcinoma

Pancreatic cancer (PC) is currently rated as the fourth leading cause of cancer-related death worldwide [7]. A tumor suppressor function for miR-202 in pancreatic carcinoma is suggested by all preclinical and clinical studies up to date [8][9][10][11]. lncRNA NORAD and ANP32E were upregulated in PC tissues and cells, whereas the miR-202-5p level was down-regulated. lncRNA NORAD competitively bound to and sequestered miR-202-5p which promoted the expression of the miR-202-5p target gene ANP32E that enhanced PC cell viability, proliferation, and self-renewal ability in vitro, as well as stimulating tumorigenesis of PC stem cells in vivo [11]. In stellate pancreatic cells, miR-202 overexpression slowed growth as well as reduced stromal extracellular membrane matrix protein expression. In orthotopic PC mouse models, both immunodeficient and immunocompetent, miR-202 overexpression reduced tumor burden, and metastasis [9]. While decreased miR-202 expression in PC tissues correlated with a poor prognosis of PC patients and an elevated cellular proliferative capacity [10], its overexpression in PC cells reduced cell proliferation and tumorigenesis by also impairing glycolysis [10]. These data suggest that overexpression of miR-202 is associated with tumor control in PC.
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide [7]. In the five articles that to date investigated the clinical role of miR-202 in HCC, lower expression levels of miR-202 were found to be associated with increased tumor size, vascular invasion, progressed tumor node and metastasis stages, and poor overall survival rates [12][13][14][15][16]. Mechanistically, in cell lines and xenograft nude mouse models, miR-202 significantly inhibited HCC cell proliferation and EMT, induced apoptosis, and suppressed tumor formation. In a xenograft nude mouse model, it was shown that the binding of miR-202 to BCL2 mRNA downregulated the expression of this protein [13]. In addition, upregulation of miR-202 in vitro inhibited cell proliferation by regulating hexokinase 2 (HK2) expression in HCC [15]. Similarly, the low-density lipoprotein receptor-related protein 6 (LRP6) was demonstrated to be a direct target of miR-202 where the latter suppressed the expression of LRP6 by binding to the 3′-untranslated region (UTR) of its mRNA, while overexpression of miR-202 in HCC cells suppressed LRP6, reducing cell proliferation and tumorigenicity [13]. Therefore, the available results indicate that lower level of miR-202 in HCC cancer (Table 1) is a potential biomarker of tumor progression.

3. miR-202 in Colorectal Tumors

Colorectal cancer (CRC) is one of the most commonly diagnosed tumors in men and women worldwide [17][18]. However, several gene expression studies in the last decades documented downregulation of miR-202 in colorectal tumors of patients relative to the adjacent healthy tissues, suggesting a potential prognostic value for miR-202 in colorectal cancer [19][20][21][22]. Lower levels of miR-202-5p in CRC tissues was found to be positively correlated with postoperative survival, and overexpression reduced the proliferation rate and inhibited tumor growth and metastasis of CRC cells [19][20][21][22]. On the other hand, a more recent study showed miR-202-5p up-regulation in CRC tumors and that its over-expression was critical for CRC cell viability [23]. However, based on the available preclinical and clinical information (Table 1), a tumor suppressive role of miR-202 in colorectal tumorigenesis appears to predominate.
Table 1 The suppressive function of miR-202 in different types of digestive tract cancers.
mir-202 Function Regulation Samples, Cell Lines, Patient Material, Animal Model Involved Downstream/Upstream Targets Ref.
(Up/Down)
Oral Cancer
suppressor down 73 oral cancer tissue, 48 normal tissues, blood samples, cell lines Sp1, protein kinase B [24]
Esophageal squamous cell carcinoma (ESCC)
suppressor down cell lines HSF2/Hsp70 [25]
  down 76 esophageal cancers (44 ESCC, 32 EAC) with adjacent normal tissues n.d. [26]
suppressor down 30 primary ESCC tissues and adjacent noncancerous tissues, cell lines p-FAK, p-Akt, LAMA1 [27]
Gastric Cancer
suppressor down 60 GC tissues and adjacent normal tissues MALAT1 [4]
suppressor down 150 GC tissues and adjacent normal tissues, mouse xenografts Gli1, γ-catenin, BCL-2 [3]
suppressor down 115 GC tissues with normal tissue samples, cell lines, mouse xenografts MALAT1, SRSF1, CCL21, mTOR [5]
Hepatocellular carcinoma
suppressor down 56 HCC samples, cell lines hexokinase 2, glycolysis [15]
suppressor down Eight pairs of snap-frozen HCC tumor, cell lines LRP6 [13]
suppressor down Tissues from 95 patients with HCC who underwent tumor, cell lines, Tumor xenograft NORAD, NORAD/miR-202-5p/TGF-β axis [14]
Gall bladder cancer
pro-tumorigenic up Blood samples of 40 GBC patients n.d. [28]
Pancreatic cancer
suppressor down PC cell lines & orthotopic mouse xenografts TGFβ1, EMT [9]
suppressor down cell lines hexokinase 2, inhibited glycolysis [10]
suppressor down cell lines Mxd1, SAP18 [8]
suppressor down 28 PC cancer and adjacent normal tissue samples, cell lines, mouse xenografts lncRNA NORAD and ANP32E [11]
Colorectal cancer
suppressor down 68 cases of CRC and 66 adjacent normal tissues, cell lines and xenografted nude mice UHRF1 [20]
suppressor down 68 CRC tissues, cell lines 1SMARCC1 [19]
suppressor down 47 pairs of CRC tissues and adjacent normal tissues, cell lines and xenografted nude mice NORAD [22]
suppressor down 98 primary CRC cancer tissues and adjacent normal tissues, cell lines, mouse xenografts ADP-ribosylation factor-like 5A [21]
pro-tumorigenic up 25 CRC tumors and adjacent normal tissues, cell lines PTEN, c-Myc AKT [23]
n.d. = no data.

This entry is adapted from the peer-reviewed paper 10.3390/ijms23115870

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