miRNA-487a Promotes Proliferation and Metastasis in Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) harbors highly metastatic properties, accounting for postoperative recurrence and metastasis. However, the mechanisms for metastasis and recurrence remain incompletely clear. This study aimed to investigate the role of hsa-miR-487a (miR-487a) in promoting the proliferation and metastasis of HCC and to elucidate the underlying molecular mechanisms. 198 HCC samples were analyzed for association between miR-487a expression and patient clinicopathological features and prognosis. The roles of miR-487a in proliferation and metastasis were validated both and The upstream regulator and downstream targets of miR-487a were determined using a dual luciferase reporter assay, chromatin immunoprecipitation and immunohistochemistry. Our results demonstrate that upregulated miR-487a correlates with a poor prognosis for HCC patients. miR-487a enhances proliferation and metastasis of HCC cells by directly binding to sprouty-related EVH1 domain containing 2 (SPRED2) or phosphoinositide-3-Kinase regulatory subunit 1 (PIK3R1). Interestingly, miR-487a mainly promotes metastasis via SPRED2 induced mitogen activated protein kinase signaling and promotes proliferation via PIK3R1 mediated AKT signaling. Transcription of miR-487a was found to be activated by up-regulated heat shock factor 1, which we previously demonstrated to be an important metastasis-associated transcription factor in a previous study. Phosphorodiamidate morpholino oligomers effectively silenced miR-487a and inhibited HCC tumor progression in mouse models. Our findings show that miR-487a, mediated by heat shock factor 1, promotes proliferation and metastasis of HCC by PIK3R1 and SPRED2 binding, respectively. Our study provides a rationale for developing miR-487a as a potential prognostic marker or a potential therapeutic target against HCC. .

miR‐4324‐RACGAP1‐STAT3‐ESR1 feedback loop inhibits proliferation and metastasis of bladder cancer

“…[3][4][5] miR-NAs can negatively regulate gene expression through a variety of mechanisms, acting as tumor suppressors or oncogenes. [6][7][8] In the present study, we demonstrated for the first time that miR-4324 was significantly downregulated in BCa, and miR-4324 suppressed important traits in BCa cells, including cell proliferation, metastasis and chemo-resistance. Mechanistically, Rac GTPase activating protein 1 (RACGAP1) was identified as a direct target gene of miR-4324.…”

“…MicroRNAs (miRNA) are small, noncoding RNA molecules that have been reported to play important roles in BCa carcinogenesis by influencing multiple cellular processes, including proliferation, metastasis, radiation sensitivity and chemo‐sensitivity . miRNAs can negatively regulate gene expression through a variety of mechanisms, acting as tumor suppressors or oncogenes …”

Epigenetically Regulated Chromosome 14q32 miRNA Cluster Induces Metastasis and Predicts Poor Prognosis in Lung Adenocarcinoma Patients

“…Three candidate miRNAs from the selected 14q32 cluster were chosen for validation: mir-323b and mir-539, which showed the highest differential expression in N ! 1 stage patients; as well as mir-487a, which was previously reported to be involved in metastasis of other cancer types (9,10). The expression of the mature (functional) forms of these miRNAs (miR-323b-3p, miR-539-5p, and miR-487a-3p; hereinafter called miR-323b, miR-539, and miR-487a, respectively) gradually increased from healthy tissue through tumors without metastasis to tumors with lymph node metastasis ( Fig.…”

MicroRNA‐331‐3p inhibits epithelial‐mesenchymal transition by targeting ErbB2 and VAV2 through the Rac1/PAK1/β‐catenin axis in non‐small‐cell lung cancer

“…As a rule, miRNAs can repress mRNA translation or promote RNA degradation by binding to the 3′‐UTRs of their targets . Numerous pieces of evidence show that abnormal expression of miRNAs and their regulation play important roles in the initiation and progression of human cancers, such as esophageal carcinoma, hepatocellular carcinoma and breast carcinoma . Some miRNAs, such as miR‐30a, are able to affect many types of malignancies and can be used as biomarkers for these tumors .…”