Molecular mechanism of the miR-7/BCL2L1/P53 signaling axis regulating the progression of hepatocellular carcinoma

Nannan Zhang; Feiran Wang; Lirong Zhu; Renan Chang; Shaffer R S Mok; Renata D'Alpino Peixoto; Weidong Tang; Zhong Chen

doi:10.21037/atm-22-5929

Molecular mechanism of the miR-7/BCL2L1/P53 signaling axis regulating the progression of hepatocellular carcinoma

Ann Transl Med. 2023 Jan 15;11(1):12. doi: 10.21037/atm-22-5929. Epub 2023 Jan 10.

Authors

Nannan Zhang^#^{1

2}, Feiran Wang^#², Lirong Zhu^#², Renan Chang², Shaffer R S Mok³, Renata D'Alpino Peixoto⁴, Weidong Tang², Zhong Chen^{1

2}

Affiliations

¹ Medical College of Nantong University, Nantong, China.
² Department of General Surgery, Affiliated Hospital of Nantong University, Nantong, China.
³ Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, FL, USA.
⁴ Centro Paulista de Oncologia (Grupo Oncoclínicas), São Paulo, Brazil.

^# Contributed equally.

Abstract

Background: To investigate the roles of miR-7 and its potential mechanisms in hepatocellular carcinoma (HCC).

Methods: The functions of miR-7 were identified and measured by MTT [3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromide], colony formation, transwell, and flow cytometry assays. A luciferase assay was applied to verify the direct binding of miR-7 on BCL2L1 3'untranslated region (3'UTR). An in vitro experiment was then used to investigate the biological effects of miR-7 and BCL2L1. A co-immunoprecipitation (COIP) assay was used to detect the protein interaction between BCL2L1 and P53.

Results: We found that miR-7 overexpression suppressed cell proliferation, migration, and invasion in HCC. BCL2L1 was also demonstrated as a direct target gene of miR-7. This study showed that BCL2L1 could partially rescue the inhibitory effect of miR-7 on the proliferation, migration, and invasion of HCC cells. Our research showed that miR-7 could inhibit the epithelial-mesenchymal transition (EMT) pathway by regulating BCL2L1. We also further confirmed that miR-7 inhibits the proliferation, migration, and invasion of Hep3B and Huh7 cells by targeting BCL2L1. Furthermore, we observed that the BCL2L1 protein interacts with the P53 protein and BCL2L1 affects the development of liver cancer through P53. We also found that BCL2L1 could promote the invasion and migration of liver cancer cells through P53 inhibition. BCL2L1 also inhibited the expression of Caspase 3/7 in hepatoma cells by inhibiting the expression of P53.

Conclusions: Our study demonstrated that miR-7/BCL2L1/P53 may serve as a regulatory molecular axis for HCC treatment. Our results suggest that miR-7/BCL2L1/P53 may have predictive value and represent a new treatment strategy for liver cancer.

Keywords: BCL2L1; P53; hepatocellular carcinoma (HCC); metastasis; miR-7.