miR-296-5p suppresses EMT of hepatocellular carcinoma via attenuating NRG1/ERBB2/ERBB3 signaling

Abstract

BackgroundAccumulation of evidence indicates that miRNAs have crucial roles in the regulation of EMT-associated properties, such as proliferation, migration and invasion. However, the underlying molecular mechanisms are not entirely illustrated. Here, we investigated the role of miR-296-5p in hepatocellular carcinoma (HCC) progression.MethodsIn vitro cell morphology, proliferation, migration and invasion were compared between HCC cell lines with up- or down-regulation of miR-296-5p. Immunofluorescence and Western blot immunofluorescence assays were used to detect the expression of EMT markers. Bioinformatics programs, luciferase reporter assay and rescue experiments were used to validate the downstream targets of miR-296-5p. Xenograft nude mouse models were established to observe tumor growth and metastasis. Immunohistochemical assays were conducted to study the relationships between miR-296-5p expression and Neuregulin-1 (NRG1)/EMT markers in human HCC samples and mice.ResultsmiR-296-5p was prominently downregulated in HCC tissues relative to adjacent normal liver tissues and associated with favorable prognosis. Overexpression of miR-296-5p inhibited EMT along with migration and invasion of HCC cells via suppressing NRG1/ERBB2/ERBB3/RAS/MAPK/Fra-2 signaling in vitro. More importantly, miR-296-5p disrupted intrahepatic and pulmonary metastasis in vivo. NRG1, as a direct target of miR-296-5p, mediates downstream biological responses. In HCC tissues from patients and mice, the levels of miR-296-5p and NRG1 also showed an inverse relationship.ConclusionsmiR-296-5p inhibited EMT-related metastasis of HCC through NRG1/ERBB2/ERBB3/RAS/MAPK/Fra-2 signaling.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0957-2) contains supplementary material, which is available to authorized users.

miR-4429Inhibits Tumor Progression and Epithelial-Mesenchymal Transition Via TargetingCDK6in Clear Cell Renal Cell Carcinoma

“…10,11 Speaking of cancer metastasis, epithelial-mesenchymal transition (EMT) is a process closely related to metastasis through which terminal differentiated epithelial cells transform to migratory mesenchymal cells during embryo development. 12 During past years, the inhibition of EMT progression by miRNAs has been identified in numerous cancers, such as in hepatocellular cancer, 13 colorectal cancer, 14 and ccRCC. 15 Furthermore, numerous miR-NAs have been identified in ccRCC to exhibit oncogenic or tumor-suppressive functions.…”

Circular RNA hsa_circ_001895 serves as a sponge of microRNA‐296‐5p to promote clear cell renal cell carcinoma progression by regulating SOX12

“…By the means of dual luciferase reporter assay and RIP, miR‐296‐5p was validated as the direct binding target for hsa_circ_001895. miR‐296‐5p is a tumor suppressor in various tumors . The present study indicated that hsa_circ_001895 knockdown inhibited ccRCC progression but induced cell apoptosis through sponging miR‐296‐5p.…”

Epithelial V‐like antigen 1 promotes hepatocellular carcinoma growth and metastasis via the ERBB‐PI3K‐AKT pathway

“…High expression of ERBB3 in certain human cancers led early on to the suggestion that it could be a therapeutic target . ERBB3 was reported to have an oncogenic role in HCC . The most fully studied target of ERBB3 is the p85 regulatory subunit of PI3K (PI3KR).…”