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MiR-103 regulates hepatocellular carcinoma growth by targeting AKAP12

Wei Xia¹, Jing Ni¹, Juhua Zhuang¹

¹Department of Nuclear Medicine, Shanghai Seventh People's Hospital, Shanghai, China.

The International Journal of Biochemistry & Cell Biology

|December 10, 2015

Abstract:

AKAP12/Gravin (A kinase anchor protein 12) belongs to the group of A-kinase scaffold proteins and functions as a tumor suppressor in some human primary cancers. While AKAP12 is found consistently downregulated in hepatocellular carcinoma (HCC), its involvement in hepatocarcinogenesis has not been fully elucidated. We identified targeting sites for miR-103 in the 3'-untranslated region (3'-UTR) of AKAP12 by bioinformatic analysis and confirm their function by a luciferase reporter gene assay. We reveal miR-103 expression to be inversely correlated with AKAP12 in HCC tissue samples and show that overexpressed miR-103 promotes cell proliferation and inhibits apoptosis by downregulating AKAP12 expression in HCC cell lines. On the other hand, repression of miR-103 suppresses proliferation and promotes apoptosis in HCC cells by increasing AKAP12. In xenografted HCC tumors, overexpression of AKAP12 suppresses tumor growth whereas overexpression of miR-103 enhances tumor growth while repressing AKAP12. Since the activation of telomerase is crucial for cells to gain immortality and proliferation ability, we investigated whether AKAP12 expression affected telomerase activity in HCC cells. Both AKAP12 overexpression and protein kinase Cα (PKCα) inhibition prevent nuclear translocation and phosphorylation of TERT and reduce telomerase activity in HCC cells. These findings indicate that miR-103 potentially acts as an oncogene in HCC by inhibiting AKAP12 expression and raise the possibility that miR-103 increases telomerase activity by increasing PKCα activity. Thus, miR-103 may represent a new potential diagnostic and therapeutic target for HCC treatment.

Insights

MicroRNA-103 (miR-103) promotes hepatocellular carcinoma (HCC) growth by downregulating the tumor suppressor AKAP12. Inhibiting miR-103 or increasing AKAP12 may offer new therapeutic strategies for HCC.

Area of Science:

Oncology
Molecular Biology
Biochemistry

Background:

A kinase anchor protein 12 (AKAP12), also known as Gravin, acts as a tumor suppressor.
AKAP12 is frequently downregulated in hepatocellular carcinoma (HCC), but its role in hepatocarcinogenesis is not fully understood.
MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression and are implicated in cancer development.

Purpose of the Study:

To investigate the role of miR-103 in HCC pathogenesis.
To elucidate the regulatory relationship between miR-103 and AKAP12 in HCC.
To explore the impact of this interaction on HCC cell proliferation, apoptosis, and telomerase activity.

Main Methods:

Bioinformatic analysis to identify miR-103 targeting sites in AKAP12 3'-UTR.
Luciferase reporter gene assay to confirm the interaction.
Quantitative analysis of miR-103 and AKAP12 expression in HCC tissues and cell lines.
In vitro experiments assessing cell proliferation and apoptosis upon modulation of miR-103 and AKAP12.
In vivo studies using HCC xenograft models.
Analysis of telomerase activity and its regulation by AKAP12 and protein kinase Cα (PKCα).

Main Results:

miR-103 directly targets AKAP12, and their expression levels are inversely correlated in HCC.
Overexpression of miR-103 promotes HCC cell proliferation and inhibits apoptosis by downregulating AKAP12.
Repression of miR-103 suppresses proliferation and induces apoptosis in HCC cells.
AKAP12 overexpression inhibits tumor growth, while miR-103 overexpression enhances it in vivo.
AKAP12 affects telomerase activity by preventing nuclear translocation and phosphorylation of TERT, potentially via PKCα modulation.

Conclusions:

miR-103 functions as an oncogene in HCC by suppressing AKAP12 expression.
miR-103 may enhance telomerase activity in HCC, contributing to cell immortality.
The miR-103/AKAP12 axis represents a potential diagnostic and therapeutic target for HCC.

Read full analysis

Keywords:

AKAP12 Hepatocellular carcinoma MiR-103 PKCα TERT Telomerase

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