MicroRNA-140-5p suppresses tumor growth and metastasis by targeting transforming growth factor β receptor 1 and fibroblast growth factor 9 in hepatocellular carcinoma

Abstract

By comparing the expression profiles of microRNAs (miRNAs) in different hepatocellular carcinoma (HCC) subtypes, we identified miR-140-5p as an HCC-related miRNA. We found that miR-140-5p was significantly decreased in HCC tissues and all of six liver cancer cell lines examined and its expression levels were correlated with multiple nodules, vein invasion, capsular formation, and differentiation, as well as overall and disease-free survival of HCC. We also found that miR-140-5p suppressed HCC cell proliferation and HCC metastasis. Multipathway reporter arrays suggested that miR-140-5p inhibited transforming growth factor b (TGF-b) and mitogen-activated protein kinase / extracellular signal-regulated kinase (MAPK/ERK) signaling. TGFB receptor 1 (TGFBR1) and fibroblast growth factor 9 (FGF9) were then characterized as the direct targets for miR-140-5p after it was found that ectopic miR-140-5p expression suppressed TGFBR1 and FGF9 expression. Silencing TGFBR1 and FGF9 by small interfering RNA (siRNA) resembled the phenotype resulting from ectopic miR-140-5p expression, while overexpression of TGFBR1 and FGF9 attenuated the effect of miR-140-5p on HCC growth and metastasis. Conclusion: These data elucidated a tumor suppressor role for miR-140-5p in HCC development and progression with therapeutic potential. Our correlation studies in clinical HCC samples further suggest that miR-140-5p could be a valuable biomarker for HCC prognosis. (HEPATOLOGY 2013;58:205-217) H epatocellular carcinoma (HCC) is one of the most common human cancers in the world, particularly in China.1 It ranks as the fifth most common malignancy and the second leading cause of cancer death worldwide, resulting in more than 695,900 deaths each year.2,3 Although its mortality decreased along with advances in surgical resection, the long-term prognosis remains unsatisfactory. For example, the 5-year survival rate is only 20% to 30% in HCC patients after surgical resection, mainly due to the high recurrence and metastasis rate. 4,5 It has been generally accepted that the invasive and metastatic potentials of HCC are mostly attributed to the differences of pathological and molecular characteristics. 6 Previously, we found a specific subtype of HCC in which the tumor was only around 5 cm in diameter with a single lesion, but the tumor grew expansively within an intact capsule or pseudocapsule. More important, the tumor possessed unique clinical and pathological characteristics. Therefore, we categorized it as solitary large hepatocellular carcinoma (SLHCC) and divided HCC into three different subtypes: SLHCC, nodular HCC (NHCC, node number !2), and small HCC (SHCC, tumor 5 cm). Further study confirmed that the metastatic potential of SLHCC was comparable to SHCC, but significantly less than NHCC.5 Additionally, SLHCC exhibited a similar long-term overall and disease-free survival to Abbreviations: FGF9, fibroblast growth factor 9; HCC, hepatocellular carcinoma; NHCC, nodular hepatocellular carcinoma; qRT-PCR, real-time quantitative PCR; SHCC, small ...

Retracted: MicroRNA‐140‐5p elevates cerebral protection of dexmedetomidine against hypoxic–ischaemic brain damage via the Wnt/β‐catenin signalling pathway

“…In our study, we found that the weight and length growth, weight ratio of the left hemisphere to the right hemisphere and the rate of reaching standard were all increased; however, decreases were recorded for total response times, total response duration and neuronal apoptosis rate in the hippocampus, when HIBD rats had been treated with DEX + miR‐140‐5p mimics or si‐Wnt1. A previous study has demonstrated that miR‐140‐5p inhibits the MAPK signalling pathway in hepatocellular carcinoma 39. DEX has also been demonstrated to protect the brain against isoflurane‐induced neuroapoptosis in the hippocampus of neonatal rats by suppressing the p38MAPK signalling pathway 40.…”

MicroRNA-140-5p inhibits cell proliferation and invasion by regulating VEGFA/MMP2 signaling in glioma

“…For example, miR-16, miR-494-3p, and miR-184 regulate glioma cell proliferation, invasion, and apoptosis and do so by differential mechanisms that target oncogenes or anti-oncogenes and by mechanisms that have been demonstrated in a xenograft animal model. [7][8][9] In this study, we found that miR-140-5p suppressed progression of human tongue cancer, hepatocellular carcinoma, and colorectal cancer [10][11][12] -processes that have not previously been investigated extensively. Specifically, there is an absence of previously published data that have demonstrated the contributions of miR-140-5p in the development of glioma.…”

The long non-coding RNA MALAT1 promotes the migration and invasion of hepatocellular carcinoma by sponging miR-204 and releasing SIRT1

“…13 Emerging evidence suggests the essential role of miRNAs in HCC development, metastasis, and prognosis. [14][15][16] Jiang et al 17 recently showed that microRNA-204 (miR-204), by directly targeting the nicotine adenine dinucleotide (NAD)-dependent deacetylase sirtuin 1 (SIRT1), suppresses the survival, stimulates the apoptosis, and inhibits the invasion and tumorigenesis of HCC cells. In spite of the therapeutic potential of miR-204, its level is downregulated in HCC tissues and negatively correlated with that of SIRT1.…”