Hepatocellular carcinoma accounts for over 80% of all primary liver cancers and is the fourth leading cause of cancer-related deaths worldwide. The five-year survival rate of hepatocellular carcinoma is only 18%, and the mortality rate is second only to pancreatic cancer. Despite recent progress in radiotherapy, chemotherapy, and surgery, current treatment for liver cancer cannot effectively improve the prognosis of patients. In addition, the characteristic of proliferative hepatocellular carcinoma is the activation of signaling pathways involved in cell proliferation. Therefore, finding an effective molecular pathway target for the treatment of liver cancer has become an urgent task.
Recently, researchers from the School of Medicine of Shanghai Jiao Tong University conducted an article titled “Syntaxin-6 promotes the progression of hepatocellular carcinoma and alters its sensitivity to chemotherapies by activating the USF2/LC3B axis” which was published in the journal Int J. Biol. Sci. The study revealed that Synaxin-6 promotes the progression of hepatocellular carcinoma and alters its sensitivity to chemotherapy by activating the USF2/LC3B axis.
Synaxin-6 (STX6) is a protein belonging to the Synaxin family, located in a cross-Golgi network and involved in various cell membrane transport events. STX6 is overexpressed in various malignant tumors in humans. However, little is currently known about its exact function and molecular mechanism in hepatocellular carcinoma.
In this study, researchers found a significant increase in the expression of STX6 in hepatocellular carcinoma tissue and associated it with poor survival. Functional acquisition and loss experiments have shown that STX6 can promote the proliferation and metastasis of liver cancer cells both in vivo and in vitro. Mechanically, STX6 is negatively regulated by upstream stimulus factor 2 (USF2). In addition, STX6 also promotes the binding of autophagosomes to lysosomes.
Importantly, researchers have demonstrated that overexpression of STX6, despite enhancing resistance to lenvatinib, makes liver cancer cells sensitive to the autophagy activator rapamycin. This study found that under USF2 regulation, STX6 accelerates the degradation of microtubule-associated protein 1 light chain 3β (LC3) by promoting autophagy flux, ultimately promotes the progression of hepatocellular carcinoma. In summary, this study suggests that the USF2-STX6-LC3B axis is a potential therapeutic target for liver cancer.
In summary, this study confirms for the first time the tumor-promoting effect of STX6 in liver cancer and confirms that high expression of STX6 promotes the proliferation and metastasis of liver cancer in vivo and in vitro, and promotes autophagy flux of liver cancer cells. The researchers also confirmed that USF2 inhibits the growth of liver cancer by negatively regulating the transcription of STX6. The findings of this study provide the first evidence of the presence of the USF2/STX6/LC3B regulatory axis in hepatocellular carcinoma, which may be a potential target for the treatment of hepatocellular carcinoma.
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Reference
Lianer Zhou et al. Syntaxin-6 promotes the progression of hepatocellular carcinoma and alters its sensitivity to chemotherapies by activating the USF2/LC3B axis. Int J Biol Sci. 2023 Jul 31;19(12):3892-3907. doi: 10.7150/ijbs.86636.