MiR-324-5p Suppresses Hepatocellular Carcinoma Cell Invasion by Counteracting ECM Degradation through Post-Transcriptionally Downregulating ETS1 and SP1

Abstract

Hepatocellular carcinoma (HCC) is one of the common malignancies, which is highly metastatic and the third common cause of cancer deaths in the world. The invasion and metastasis of cancer cells is a multistep and complex process which is mainly initiated by extracellular matrix (ECM) degradation. Aberrant expression of microRNA has been investigated in HCC and shown to play essential roles during HCC progression. In the present study, we found that microRNA-324-5p (miR-324-5p) was downregulated in both HCC cell lines and tissues. Ectopic miR-324-5p led to the reduction of HCC cells invasive and metastatic capacity, whereas inhibition of miR-324-5p promoted the invasion of HCC cells. Matrix metalloproteinase 2 (MMP2) and MMP9, the major regulators of ECM degradation, were found to be downregulated by ectopic miR-324-5p, while upregulated by miR-324-5p inhibitor. E26 transformation-specific 1 (ETS1) and Specificity protein 1 (SP1), both of which could modulate MMP2 and MMP9 expression and activity, were presented as the direct targets of and downregulated by miR-324-5p. Downregulation of ETS1 and SP1 mediated the inhibitory function of miR-324-5p on HCC migration and invasion. Our study demonstrates that miR-324-5p suppresses hepatocellular carcinoma cell invasion and might provide new clues to invasive HCC therapy.

Eukaryotic elongation factor 2 kinase promotes angiogenesis in hepatocellular carcinoma via PI3K/Akt and STAT3

“…[36][37][38] SP1 is involved in tumor growth and invasion of HCC. 39,40 KLF5 and SP1 are also potential tumor prognosis markers in other types of cancers (i.e., breast cancers) where eEF2K is highly expressed, 35,41,42 hence the regulation of KLF5 and SP1 by eEF2K may not only be limited to HCC.…”

MiR-324-5p reduces viability and induces apoptosis in gastric cancer cells through modulating TSPAN8

“…MiR‐324‐5p could reduce the cell survival rate and increase the cell cycle arrest in glioma cells . Moreover, miR‐324‐5p has also been proved to inhibit cancer cell invasion and migration in breast cancer and hepatocellular carcinoma . In multiple myeloma (MM), miR‐324‐5p was decreased, and overexpressed miR‐324‐5p significantly reduced cancer cell growth and increased the sensitivity of MM cells to bortezomib in vit r o .…”

“…[20] Moreover, miR-324-5p has also been proved to inhibit cancer cell invasion and migration in breast cancer and hepatocellular carcinoma. [13,21] In multiple myeloma (MM), miR-324-5p was decreased, and overexpressed miR-324-5p significantly reduced cancer cell growth and increased the sensitivity of MM cells to bortezomib in vitro. [22] The functional role of miR-324-5p in gastric cancer was first proved in this study.…”

“…MiRNAs existed in RNA‐induced silencing complex (RISC) could inhibit the translation and induce degradation of the target mRNAs through interacting with mRNA 3′‐untranslated regions (3′‐UTR) . MiR‐324‐5p has been proved to involve in many human diseases by modulating its downstream targets, such as mitochondrial fission regulator 1 (Mtfr1), E26 transformation‐specific 1 (ETS1) and Specificity protein 1 (SP1) . The bioinformatics analysis showed that the potential binding sites of miR‐324‐5p presented in the 3′‐UTR of Tetraspanin 8 (TSPAN8), suggesting the possible interaction between miR‐324‐5p and TSPAN8.…”

“…[11] MiR-324-5p has been proved to involve in many human diseases by modulating its downstream targets, such as mitochondrial fission regulator 1 (Mtfr1), E26 transformation-specific 1 (ETS1) and Specificity protein 1 (SP1). [12,13] The bioinformatics analysis showed that the potential binding sites of miR-324-5p presented in the 3 0 -UTR of Tetraspanin 8 (TSPAN8), suggesting the possible interaction between miR-324-5p and TSPAN8. More importantly, TSPAN8 was confirmed to induce cell growth and invasion in gastric cancer.…”