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CSF3R-AS promotes hepatocellular carcinoma progression and sorafenib resistance through the CSF3R/JAK2/STAT3 positive
Ziyang Feng1,2,3, Yan Gao1, Changjing Cai1
1Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
Abstract:
Antisense circular RNA is a special type of circular RNA that is derived from the antisense complementary strand of parental mRNA. However, the function of antisense circRNA in hepatocellular carcinoma (HCC) is still unclear. Here, we reported that CSF3R-AS was upregulated in HCC and correlated with a poor prognosis. CSF3R-AS promoted the proliferation, angiogenesis, and metastasis of HCC, and inhibited apoptosis. Mechanistically, CSF3R-AS has a 180-base complementary pairing sequence with its parental mRNA CSF3R, which can directly bind to CSF3R and recruit RBMS3 to stabilize its parental mRNA, and finally activate JAK2/STAT3 signaling pathway. Interestingly, STAT3 can act as a transcription factor of CSF3R-AS, which means that there is a CSF3R-AS/CSF3R/JAK2/STAT3 positive feedback loop in HCC. Finally, the CSF3R-AS/CSF3R/JAK2/STAT3 positive feedback loop was also activated in HCC sorafenib-resistant cells, and blocking this loop was expected to improve the sensitivity of HCC to sorafenib. These findings suggested that the CSF3R-AS/CSF3R/JAK2/STAT3 positive feedback loop could promote HCC progression and sorafenib resistance. Blocking this loop is expected to provide new research directions and therapy targets for HCC.
Insights
Antisense circular RNA CSF3R-AS promotes hepatocellular carcinoma (HCC) growth and metastasis by stabilizing CSF3R mRNA and activating the JAK2/STAT3 pathway. This feedback loop also drives sorafenib resistance in HCC.
Area of Science:
- Molecular Biology
- Oncology
- RNA Biology
Background:
- Antisense circular RNAs (circRNAs) are emerging regulators of gene expression.
- The role of antisense circRNAs in hepatocellular carcinoma (HCC) remains largely unexplored.
Purpose of the Study:
- To investigate the function of antisense circRNA CSF3R-AS in HCC.
- To elucidate the underlying molecular mechanisms and therapeutic potential in HCC.
Main Methods:
- Quantitative real-time PCR to assess CSF3R-AS expression.
- Cell proliferation, angiogenesis, and metastasis assays.
- Western blotting and luciferase reporter assays to investigate signaling pathways.
Main Results:
- CSF3R-AS was significantly upregulated in HCC tissues and correlated with poor prognosis.
- CSF3R-AS promoted HCC cell proliferation, angiogenesis, and metastasis while inhibiting apoptosis.
- CSF3R-AS directly binds to CSF3R mRNA, stabilizing it and activating the JAK2/STAT3 pathway, forming a positive feedback loop.
Conclusions:
- The CSF3R-AS/CSF3R/JAK2/STAT3 positive feedback loop drives HCC progression and sorafenib resistance.
- Targeting this loop presents a potential therapeutic strategy for HCC treatment and overcoming drug resistance.
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