MicroRNA-148a Suppresses Tumor Cell Invasion and Metastasis by Downregulating ROCK1 in Gastric Cancer

Department of Gastric Cancer and Soft Tissue Sarcomas, Fudan University Shanghai Cancer Center and Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Clinical Cancer Research (Impact Factor: 8.72). 12/2011; 17(24):7574-83. DOI: 10.1158/1078-0432.CCR-11-1714
Source: PubMed


MicroRNAs (miRNA) have been documented playing a critical role in cancer development and progression. In this study, we investigate the role of miR-148a in gastric cancer metastasis.
We examined miR-148a levels in 90 gastric cancer samples by qRT-PCR and analyzed the clinicopathologic significance of miR-148a expression. The gastric cancer cells stably expressing miRNA-148a were analyzed for migration and invasion assays in vitro and metastasis assays in vivo; the target genes of miR-148a were further explored.
We found that miR-148a expression was suppressed by more than 4-fold in gastric cancer compared with their corresponding nontumorous tissues, and the downregulated miR-148a was significantly associated with tumor-node-metastasis (TNM) stage and lymph node-metastasis. Functional assays showed that overexpression of miR-148a suppressed gastric cancer cell migration and invasion in vitro and lung metastasis formation in vivo. In addition, overexpression of miR-148a in GC cells could reduce the mRNA and protein levels of ROCK1, whereas miR-148a silencing significantly increased ROCK1 expression. Luciferase assays confirmed that miR-148a could directly bind to the 2 sites of 3' untranslated region of ROCK1. Moreover, in gastric cancer tissues, we observed an inverse correlation between miR-148a and ROCK1 expression. Knockdown of ROCK1 significantly inhibited gastric cancer cell migration and invasion resembling that of miR-148a overexpression. We further found that ROCK1 was involved in miR-148a-induced suppression of gastric cancer cell migration and invasion.
miR-148a functions as a tumor metastasis suppressor in gastric cancer, and downregulation of miR-148a contributes to gastric cancer lymph node-metastasis and progression. miR-148a may have a therapeutic potential to suppress gastric cancer metastasis.

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    • "MiR-148a functions as a tumor suppressor in cancer cells. It was reported that miR-148a functions as a tumor metastasis suppressor in gastric cancer and downregulation of miR-148a contributes to gastric cancer lymph node-metastasis and progression likely via SMAD2 [25] [26]. Moreover, miR-148a acts as a tumor suppressor by targeting IGF-IR and IRS1 [27]. "
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    ABSTRACT: Breast cancer is the most common malignant diseases in women. miR-148a plays an important role in regulation of cancer cell proliferation and cancer invasion and down-regulation of miR-148a has been reported in both estrogen receptor (ER) positive and triple-negative (TN) breast cancer. However, the regulation mechanism of miR-148a is unclear. The role of estrogen signaling, a signaling pathway is important in development and progression of breast cancer. Therefore, we speculated that E2 may regulate miR-148a through G-protein-coupled estrogen receptor-1 (GPER). To test our hypothesis, we checked the effects of E2 on miR-148a expression in ER positive breast cancer cell MCF-7 and TN cancer cell MDA-MB-231. Then we used GPER inhibitor G15 to investigate whether GPER is involved in regulation of E2 on miR-148a. Furthermore, we analyzed whether E2 affects the expression of HLA-G, which is a miR-148a target gene through GPER. The results showed that E2 induces the level of miR-148a in MCF-7 and MDA-MB-231 cells, GPER mediates the E2-induced increase in miR-148a expression in MCF-7 and MDA-MB-231 cells and E2-GPER regulates the expression of HLA-G by miR-148a. In conclusion, our findings offer important new insights into the ability of estrogenic GPER signaling to trigger HLA-G expression through inhibiting miR-148a that supports immune evasion in breast cancer.
    Preview · Article · Jul 2014 · Biochemical and Biophysical Research Communications
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    • "However, other studies revealed that miR-148a was significantly down-regulated in gastrointestinal cancers, and it repressed gastric cancer metastasis by targeting ROCK1 (Ref. 104). "
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    ABSTRACT: Carcinoma of the stomach is one of the most prevalent cancer types in the world. Although the incidence of gastric cancer is declining, the outcomes of gastric cancer patients remain dismal because of the lack of effective biomarkers to detect early gastric cancer. Modern biomedical research has explored many potential gastric cancer biomarker genes by utilising serum protein antigens, oncogenic genes or gene families through improving molecular biological technologies, such as microarray, RNA-Seq and the like. Recently, the small noncoding microRNAs (miRNAs) have been suggested to be critical regulators in the oncogenesis pathways and to serve as useful clinical biomarkers. This new class of biomarkers is emerging as a novel molecule for cancer diagnosis and prognosis, including gastric cancer. By translational suppression of target genes, miRNAs play a significant role in the gastric cancer cell physiology and tumour progression. There are potential implications of previously discovered gastric cancer molecular biomarkers and their expression modulations by respective miRNAs. Therefore, many miRNAs are found to play oncogenic roles or tumour-suppressing functions in human cancers. With the surprising stability of miRNAs in tissues, serum or other body fluids, miRNAs have emerged as a new type of cancer biomarker with immeasurable clinical potential.
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    • "The present results are consistent with the majority of studies that describe miR-196a to be highly expressed in GC. A low expression of miR-148a has also been confirmed in certain human cancers and was associated with the cancer patient’s prognosis by regulating its target genes (27–29). miR-148a may act as candidate biomarker in human cancer (30,31). "
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    ABSTRACT: Gastric cancer (GC) is one of the most common malignant tumors worldwide. No fundamental improvements in the five-year survival rates of patients with GC have been reported due to a low early diagnosis rate. Therefore, the identification of novel biomarkers is urgently required for an early diagnosis of GC. A total of 86 patients were selected for the present study, including 44 patients with early stage GC (T1-T2 according to TNM staging criteria) and 42 normal gastric mucosa samples from non-cancer patients as controls. A total of 18 samples were used for the microRNA (miRNA) microarray experiments, including nine early GC and nine normal gastric mucosa samples. Bioinformatics algorithms, significant analysis of microarray (SAM), top scoring pair (TSP) and statistical receiver operating characteristic curves were used to identify the best signatures. Finally, quantitative PCR was used to validate the candidate biomarkers for early gastric cancer in the test samples (35 cancer and 33 normal samples). Using the SAM algorithm, 14 differential miRNAs were selected as candidate biomarkers. Using the TSP algorithm, hsa-miR-196a and hsa-miR-148a were obtained as a signature to differentiate between the early GC and normal samples. A coincidental result was observed in the test samples. hsa-miR-196a was upregulated and hsa-miR-148a was downregulated in the early GC samples. hsa-miR-196a and hsa-miR-148a have the potential to serve as candidate biomarkers for early GC.
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