Tumor‐suppressive microRNA‐10a inhibits cell proliferation and metastasis by targeting Tiam1 in esophageal squamous cell carcinoma

Abstract

Aberrant microRNAs (miRNAs) expressions could contribute to the progression of numerous cancers, including esophageal squamous cell carcinoma, while miR‐10a participates in multiple biological processes on cancers. However, the molecular mechanism of miR‐10a in esophageal squamous cell carcinoma (ESCC) has not been investigated. Herein, miR‐10a was significantly reduced in ESCC clinical tissues and ESCC cell lines (EC109 and TE‐3). In addition, immunohistochemistry indicated that the expressions of α‐SMA, Ki‐67, and PCNA in tumor tissues were higher than that of controls. In vitro, overexpression of miR‐10a dramatically suppressed cell proliferation and enhanced cell apoptosis, while the decrease of miR‐10a expressed the opposite outcome. Specially, overexpression of miR‐10a caused a G0/G1 peak accumulation. Moreover, miR‐10a also negatively regulated ESCC cell migration and invasion. Furthermore, targetscan bioinformatics predictions and the dual‐luciferase assay confirmed that Tiam1 was a direct target gene of miR‐10a. The statistical analysis showed Tiam1 was negatively in correlation with miR‐10a in ESCC patient samples. And silencing Tiam1 could lead to a decline on cell growth, invasion, and migration in ESCC cell lines, while it could enhance cell apoptosis and cause a G0/G1 peak accumulation. In vivo, it revealed that miR‐10a notably decreased the tumor growth and metastasis in xenograft model and pulmonary metastasis model. And it showed a lower expressions of Tiam1 in the miR‐10a mimics group by immunohistochemistry. Taken together the results, they indicated that miR‐10a might function as a novel tumor suppressor in vitro and in vivo via targeting Tiam1, suggesting miR‐10a to be a candidate biomarker for the ESCC therapy.

<p>High Tiam1 expression predicts positive lymphatic metastasis and worse survival in patients with malignant solid tumors: a systematic review and meta-analysis</p>

“…Third, several studies also suggested that Tiam1 overexpression could promote the in vitro proliferation of malignant cells and in vivo growth of tumor. [24][25][26][27] As above, it can be easily deduced that Tiam1 expression in cancer cells is required for facilitating tumor growth, invasion, metastasis and chemo-resistance, which supports the prognostic value of Tiam1. Therefore, Tiam1 in tumor cells may be an attractive therapeutic target.…”

“…T-cell lymphoma invasion and metastasis-inducing factor 1 (Tiam1), a specific guanine nucleotide exchange factor, a member of the Rho GTPase family, was first discovered by Habets et al and identified as an invasion and metastasisrelated gene in mice with aggressive T-cell lymphoma. 4,5 The TIAM1 gene is located in the q22 band of chromosome 21 and the centromeric end of the AML 21 gene and contains 2 exons (~7.3 kb) separated by 1 intron (14 kb) 6 Tiam1 is mainly expressed in normal brain and testis tissues with only minimal or no expressions detected in other normal tissues 7 Additionally, Tiam1 is highly expressed in various cancers as well, 6,[8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] and its overexpression in cancer cells could contribute to proliferation, [24][25][26][27] invasion and metastasis, [28][29][30][31] angiogenesis 32 and chemo-resistance of cancer cells 33 Of note, Tiam1 expressed in tumor stromal microenvironment also plays a role in regulating tumor invasion, metastasis and chemo-resistance. Cancer-associated fibroblast (CAF) is a major stromal cell in cancer stromal microenvironment.…”

MicroRNA‐488‐3p inhibits proliferation and induces apoptosis by targeting ZBTB2 in esophageal squamous cell carcinoma

“…One of the major regulatory mechanisms of miRNAs is the inhibition of gene expression through binding to the 3′UTR of target mRNAs . A number of studies have reported that miRNAs exerted antitumor functions in cancers in such manner, including in ESCC . MiR‐488‐3p has also been reported to inhibit tumor progression by targeting oncogene in glioma and melanoma .…”

“…8,9,14 A number of studies have reported that miRNAs exerted antitumor functions in cancers in such manner, 10,35 including in ESCC. 4,36 MiR-488-3p has also been reported to inhibit tumor progression by targeting oncogene in glioma and melanoma. 15,30 In our study, we predicted through TargetScan the potential targets for miR-488-3p, among which we chose ZBTB2 for further exploration.…”

Emerging Role of Non-Coding RNAs in Esophageal Squamous Cell Carcinoma

“…Many such studies have been published so far, which reveal miRNAs as tumor suppressors or oncogenes (Table 1). For example, miR-146a, miR-133b, miR-106b-3p, miR-219-5p, miR-206, miR-384, miR-455-5p, miR-128, miR-145-3p/5p, miR-10b-3p, miR-874-3p, miR-10a, miR-365, miR-301a, miR-6775-3p, miR-139-5p, miR-516b, miR-449a-5p, miR-125b, miR-433-3p, miR-370, miR-133b, miR-30a-3p/5p, miR-34a, miR-196a, and miR-125b-5p have been shown to act as tumor suppressors by inhibiting ESCC cell proliferation, promoting apoptosis by directly targeting oncogenes, or antagonizing pro-cancer signaling pathways [29,33,35,[40][41][42][43][44][45][46][47][48][49][50][51][52][54][55][56][57][58][60][61][62][63]110,133]. In contrast, pro-oncogenes such as miR-141, miR-21, miR-10b-3p, miR-424, miR-675-3p, miR-543, miR-135, miR-23b-3p, miR-502, miR-21-5p, and miR-548k have been reported to play contrasting roles in promoting cell proliferation or suppressing apoptosis in ESCC [47,[64][65][66][67][68][69][70][71][72][73].…”