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Published on: April 18, 2025
PHACTR4 regulates proliferation, migration and invasion of human hepatocellular carcinoma by inhibiting IL-6/Stat3
1Department of Hepatobiliary Surgery, Zaozhuang Mining Group Central Hospital, Zaozhuang City, Shandong Province, China. zengqin_zhang@163.com.
Objective:
Phosphatase and actin regulator 4 (PHACTR4) is one member of the largely uncharacterized PHACTR family of protein phosphatase 1 (PP1)-and actin-binding proteins. PHACTR4 is significantly deleted or mutant in many tumor subtypes, such as breast, colorectal, lung, neural, ovarian, and renal cancers. However, the role of PHACTR4 in human hepatocellular carcinoma (HCC) is completely unknown.
Materials And Methods:
Ten paired HCC tissues and adjacent non-cancerous tissues were used to detect the expression PHACTR4. Real-time PCR was used to detect the mRNA level of PHACTR4 in clinic samples. The protein level of PHACTR4 was determined by Western blot. Retrovirus-based gene transduction was used to generate Flag-tagged PHACTR4 HepG2 stable cell line. BrdU assay was used to determine the cell growth of HepG2 cells. The cell cycle distribution was detected by flow cytometry assay. In vitro scratch wounding and Matrigel invasion assays were used to test the migration and invasion ability of HepG2 cells.
Results:
The expression of PHACTR4 was noticeably decreased in clinical HCC tissues, compared to the non-tumoral tissues. Overexpression of PHACTR4 inhibited HCC cells proliferation, colony formation, migration and invasion, and resulted in significant cycle arrest. PHACTR4 attenuated both constitutive and IL-6-induced phosphorylation of signal transducer and activator of transcription 3 (Stat3), and inhibited Stat3 downstream genes expression.
Conclusions:
Overall, our results suggest that PHACTR4 is a tumor suppressor in HCC by inhibiting IL-6/ Stat3 pathway.
Insights
Phosphatase and actin regulator 4 (PHACTR4) acts as a tumor suppressor in hepatocellular carcinoma (HCC). Its decreased expression in HCC inhibits cell proliferation, migration, invasion, and the IL-6/Stat3 signaling pathway.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Phosphatase and actin regulator 4 (PHACTR4) is part of the PHACTR protein family, known for binding protein phosphatase 1 (PP1) and actin.
- PHACTR4 alterations are observed in various cancers, but its role in hepatocellular carcinoma (HCC) remains unexplored.
Purpose of the Study:
- To investigate the function and mechanism of PHACTR4 in human hepatocellular carcinoma (HCC).
Main Methods:
- Quantitative real-time PCR and Western blotting were used to assess PHACTR4 expression in HCC tissues and cell lines.
- Cell proliferation, cell cycle, migration, and invasion assays were performed using a PHACTR4-overexpressing HepG2 cell line.
- The study examined the effect of PHACTR4 on the IL-6/Stat3 signaling pathway.
Main Results:
- PHACTR4 expression was significantly downregulated in HCC tissues compared to adjacent non-cancerous tissues.
- Overexpression of PHACTR4 suppressed HCC cell proliferation, colony formation, migration, and invasion, leading to cell cycle arrest.
- PHACTR4 attenuated IL-6-induced signal transducer and activator of transcription 3 (Stat3) phosphorylation and inhibited Stat3 downstream gene expression.
Conclusions:
- PHACTR4 functions as a tumor suppressor in HCC.
- The tumor-suppressive role of PHACTR4 in HCC is mediated through the inhibition of the IL-6/Stat3 signaling pathway.
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