Combined RNAi of CTTN and FGF2 Modulates Cell Migration, Invasion and G1/S Transition of Hepatocellular Carcinoma through Ras/ERK Signaling Pathway

Jiaming Zhou; Jiaxuan Liu; Tiejun Li; Qiang Zhong; Hongyu Yu

doi:10.2174/0115680096254722231025110912

Combined RNAi of CTTN and FGF2 Modulates Cell Migration, Invasion and G1/S Transition of Hepatocellular Carcinoma through Ras/ERK Signaling Pathway

Curr Cancer Drug Targets. 2023 Nov 29. doi: 10.2174/0115680096254722231025110912. Online ahead of print.

Authors

Jiaming Zhou¹, Jiaxuan Liu², Tiejun Li¹, Qiang Zhong³, Hongyu Yu³

Affiliations

¹ Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu, China.
² Department of Pathology, Shanghai Chest Hospital, Shanghai 200003, China.
³ Department of Pathology, Second Affiliated Hospital of Naval Medical University, Shanghai 200003, China.

PMID: 38031266
DOI: 10.2174/0115680096254722231025110912

Abstract

Background: Most patients with hepatocellular carcinoma (HCC) die of rapid progression and distant metastasis. Gene therapy represents a promising choice for HCC treatment, but the effective targeted methods are still limited.

Objective: CTTN/cortactin plays a key role in actin polymerization and regulates cytoskeleton remodeling. However, the interaction network of CTTN in HCC is not well understood.

Methods: siRNA was designed for CTTN silencing and Affymetrix GeneChip sequencing was used to obtain the gene profile after CTTN knockdown in the HCC cell line SMMC-7721. Potential interacting genes of CTTN were identified using qRT-PCR. The inhibition on HCC by combined RNA interference (RNAi) of CTTN and fibroblast growth factor 2 (FGF2) was detected.

Results: A total of 1,717 significantly altered genes were screened out and 12 potential interacting genes of CTTN were identified. The interaction of CTTN and FGF2 was validated and combined RNAi of CTTN and FGF2 achieved a synergistic effect, leading to better inhibition of HCC cell migration, invasion and G1/S transition than single knockdown of CTTN or FGF2. Mechanistically, combined RNAi of CTTN and FGF2 modulated the Ras/ERK signaling pathway. In addition, the EMT epithelial marker E-cadherin was upregulated while the mesenchymal marker Vimentin and cell cycle protein Cyclin D1 were downregulated after combined RNAi of CTTN and FGF2. Additionally, qRT-PCR and immunohistochemical staining showed that both CTTN and FGF2 were highly expressed in metastatic HCC tissues.

Conclusion: Combined RNAi of CTTN and FGF2 may be a novel and promising intervention strategy for HCC invasion and metastasis.

Keywords: CTTN; FGF2; G1/S transition; Ras/ERK; invasion; migration.