RFX6 facilitates aerobic glycolysis‐mediated growth and metastasis of hepatocellular carcinoma through targeting PGAM1

Qiu, Zhiyu; Wang, Chenwei; Huang, Pinzhu; Yuan, Yichuan; Shi, Yunxing; Lin, Zhu; Huang, Zhenkun; Zuo, Dinglan; Qiu, Jiliang; He, Wei; Shen, Jingxian; Niu, Yi; Yuan, Yunfei; Li, Binkui

doi:10.1002/ctm2.1511

Cited by 6 publications

(1 citation statement)

References 52 publications

(125 reference statements)

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“…In contrast to normal cells, the malignant ones tend to induce and highly rely on aerobic glycolysis, which is termed the Warburg effect and is associated with the production of lactates [223]. Studies have demonstrated that molecules that enhance aerobic glycolysis, promote tumor progression as well [224,225]. Importantly, lactates cause the acidification of TME, and, as a result, infiltrating immune cells undergo certain adaptations to function under these conditions.…”

Section: Potential Future Targetsmentioning

confidence: 99%

New Opportunities in the Systemic Treatment of Hepatocellular Carcinoma—Today and Tomorrow

Becht,

Kiełbowski,

Wasilewicz

2024

IJMS

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Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Liver cirrhosis, hepatitis B, hepatitis C, and non-alcoholic fatty liver disease represent major risk factors of HCC. Multiple different treatment options are available, depending on the Barcelona Clinic Liver Cancer (BCLC) algorithm. Systemic treatment is reserved for certain patients in stages B and C, who will not benefit from regional treatment methods. In the last fifteen years, the arsenal of available therapeutics has largely expanded, which improved treatment outcomes. Nevertheless, not all patients respond to these agents and novel combinations and drugs are needed. In this review, we aim to summarize the pathway of trials investigating the safety and efficacy of targeted therapeutics and immunotherapies since the introduction of sorafenib. Furthermore, we discuss the current evidence regarding resistance mechanisms and potential novel targets in the treatment of advanced HCC.

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Section: Potential Future Targetsmentioning

confidence: 99%

New Opportunities in the Systemic Treatment of Hepatocellular Carcinoma—Today and Tomorrow

Becht,

Kiełbowski,

Wasilewicz

2024

IJMS

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Therapeutic targeting of PLK1 in TERT promoter‐mutant hepatocellular carcinoma

Tang,

Hu,

Sang

et al. 2024

Clinical & Translational Med

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BackgroundHotspot mutations in the promoter of telomerase reverse transcriptase (TERT) gene are the most common genetic variants in hepatocellular carcinoma (HCC) and associated with poor prognosis of the disease. However, no drug was currently approved for treating TERT promoter mutation positive HCC patients. Here, we aim to explore the potential therapeutic strategy for targeting TERT promoter mutation in HCC.MethodsThe Liver Cancer Model Repository database was used for screening potential drugs to selectively suppress the growth of TERT promoter mutant HCC cells. RNA‐seq, CRISPR‐Cas9 technology and siRNA transfection were performed for mechanistic studies. Cell counting kit‐8 (CCK8) assay and the xenograft tumour models were used for cell growth detection in vitro and in vivo, respectively. Cell apoptosis and cell cycle arrest were analysed by Annexin V‐FITC staining and/or propidium iodide staining.ResultsPLK1 inhibitors were remarkably more sensitive to HCC cells harbouring TERT promoter mutation than wild‐type cells in vitro and in vivo, which were diminished after TERT promoter mutation was edited to the wild‐type nucleotide. Comparing the HCC cells with wild‐type promoter of TERT, PLK1 inhibitors specifically downregulated Smad3 to regulate TERT for inducing apoptosis and G2/M arrest in TERT mutant HCC cells. Moreover, knockout of Smad3 counteracted the effects of PLK1 inhibitors in TERT mutant HCC cells. Finally, a cooperative effect of PLK1 and Smad3 inhibition was observed in TERT mutant cells.ConclusionsPLK1 inhibition selectively suppressed the growth of TERT mutant HCC cells through Smad3, thus contributed to discover a novel therapeutic strategy to treat HCC patients harbouring TERT promoter mutations.Key points TERT promoter mutation confers sensitivity to PLK1 inhibitors in HCC. The selective growth inhibition of TERT mutant HCC cells induced by PLK1 inhibitor was mediated by Smad3. Combined inhibition of PLK1 and Smad3 showed a cooperative anti‐tumor effect in TERT mutant HCC cells.

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JAM2 is a prognostic biomarker and inhibits proliferation, metastasis and epithelial–mesenchymal transition in lung adenocarcinoma

Dong,

Zhang,

Xie

et al. 2024

The Journal of Gene Medicine

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BackgroundJunctional adhesion molecule 2 (JAM2) plays a pivotal role in various biological processes, including proliferation, metastasis and angiogenesis, contributing to tumor progression. While previous studies have highlighted the polarizing functions of JAM2 in different cancer types, its specific role in lung adenocarcinoma (LUAD) remains unclear.MethodsIn this study, we harnessed multiple public databases to analyze the expression and prognostic significance of JAM2 in LUAD. Using the Linkedomics database, Matescape database and R package, we explored the associated genes, the potential biological functions and the impact of JAM2 on the tumor microenvironment. Our findings from public databases were further validated using real‐time quantitative PCR, western blot and immunohistochemistry. Additionally, in vitro experiments were conducted to assess the influence of JAM2 on LUAD cell proliferation, invasion, migration, apoptosis and epithelial–mesenchymal transition. Furthermore, we established a xenograft model to investigate the in vivo effects of JAM2 on tumorigenesis.ResultsOur results revealed a significant downregulation of JAM2 in LUAD, and patients with low JAM2 expression exhibited unfavorable overall survival outcomes. Functional enrichment analysis indicated that JAM2 may be associated with processes such as cell adhesion, extracellular matrix, cell junctions and regulation of proliferation. Notably, increased JAM2 expression correlated with higher tumor microenvironment scores and reduced immune cell abundance. Furthermore, overexpression of JAM2 induced apoptosis, suppressed tumor proliferation and exhibited potential inhibitory effects on tumor invasion and migration through the modulation of epithelial–mesenchymal transition. Additionally, in vivo experiments confirmed that JAM2 overexpression led to a reduction in tumor growth.ConclusionOverall, our study highlights the clinical significance of low JAM2 expression as a predictor of poor prognosis in LUAD patients. Moreover, JAM2 was found to exert inhibitory effects on various aspects of tumor progression. Consequently, JAM2 emerges as a promising prognostic biomarker and a potential therapeutic target for LUAD patients.

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RFX6 facilitates aerobic glycolysis‐mediated growth and metastasis of hepatocellular carcinoma through targeting PGAM1

Cited by 6 publications

References 52 publications

New Opportunities in the Systemic Treatment of Hepatocellular Carcinoma—Today and Tomorrow

New Opportunities in the Systemic Treatment of Hepatocellular Carcinoma—Today and Tomorrow

Therapeutic targeting of PLK1 in TERT promoter‐mutant hepatocellular carcinoma

JAM2 is a prognostic biomarker and inhibits proliferation, metastasis and epithelial–mesenchymal transition in lung adenocarcinoma

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