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CSF3R-AS通过CSF3R/JAK2/STAT3正反馈环促进肝细胞癌进展及索拉非尼耐药。

CSF3R-AS promotes hepatocellular carcinoma progression and sorafenib resistance through the CSF3R/JAK2/STAT3 positive feedback loop.

作者信息

Feng Ziyang, Gao Yan, Cai Changjing, Tan Jun, Liu Ping, Chen Yihong, Deng Gongping, Ouyang Yanhong, Liu Xuewen, Cao Ke, Zeng Shan, Han Ying, Deng Xiangying, Shen Hong

机构信息

Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.

Department of Oncology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.

出版信息

Cell Death Dis. 2025 Mar 28;16(1):217. doi: 10.1038/s41419-025-07558-4.

DOI:10.1038/s41419-025-07558-4
PMID:40155591
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11953311/
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.

摘要

反义环状RNA是一种特殊类型的环状RNA，它来源于亲本mRNA的反义互补链。然而，反义环状RNA在肝细胞癌（HCC）中的功能仍不清楚。在此，我们报道CSF3R-AS在HCC中上调，并与预后不良相关。CSF3R-AS促进HCC的增殖、血管生成和转移，并抑制细胞凋亡。机制上，CSF3R-AS与其亲本mRNA CSF3R有一个180个碱基的互补配对序列，它可以直接结合CSF3R并招募RBMS3来稳定其亲本mRNA，最终激活JAK2/STAT3信号通路。有趣的是，STAT3可以作为CSF3R-AS的转录因子，这意味着在HCC中存在一个CSF3R-AS/CSF3R/JAK2/STAT3正反馈环。最后，CSF3R-AS/CSF3R/JAK2/STAT3正反馈环在HCC索拉非尼耐药细胞中也被激活，阻断这个环有望提高HCC对索拉非尼的敏感性。这些发现表明，CSF3R-AS/CSF3R/JAK2/STAT3正反馈环可促进HCC进展和索拉非尼耐药。阻断这个环有望为HCC提供新的研究方向和治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3abf/11953311/7ca171faf583/41419_2025_7558_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3abf/11953311/addb62807d78/41419_2025_7558_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3abf/11953311/453614b5fe88/41419_2025_7558_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3abf/11953311/3d69f45d41fd/41419_2025_7558_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3abf/11953311/77572910ec67/41419_2025_7558_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3abf/11953311/0464845b6b16/41419_2025_7558_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3abf/11953311/73182f151758/41419_2025_7558_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3abf/11953311/7ca171faf583/41419_2025_7558_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3abf/11953311/addb62807d78/41419_2025_7558_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3abf/11953311/453614b5fe88/41419_2025_7558_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3abf/11953311/3d69f45d41fd/41419_2025_7558_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3abf/11953311/77572910ec67/41419_2025_7558_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3abf/11953311/0464845b6b16/41419_2025_7558_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3abf/11953311/73182f151758/41419_2025_7558_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3abf/11953311/7ca171faf583/41419_2025_7558_Fig7_HTML.jpg

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