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LARP4B通过激活SPINK1介导的EGFR通路促进肝细胞癌进展并削弱索拉非尼疗效。

LARP4B promotes hepatocellular carcinoma progression and impairs sorafenib efficacy by activating SPINK1-mediated EGFR pathway.

作者信息

Wang Chuanxu, Dong Rui, Yang Feicheng, Zheng Lu, Liu Yingling, Yan Yue, Zhang Mengjie, Ni Bing, Li Jing

机构信息

Department of Hepatobiliary Surgery, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, China.

Department of Pathophysiology, Third Military Medical University (Army Medical University), Chongqing, China.

出版信息

Cell Death Discov. 2024 May 1;10(1):208. doi: 10.1038/s41420-024-01985-6.

DOI:10.1038/s41420-024-01985-6
PMID:38693111
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11063073/
Abstract

La-related proteins (LARPs) regulate gene expression by binding to RNAs and exhibit critical effects on disease progression, including tumors. However, the role of LARP4B and its underlying mechanisms in the progression of hepatocellular carcinoma (HCC) remain largely unclear. In this study, we found that LARP4B expression is upregulated and correlates with poor prognosis in patients with HCC. Gain- and loss-of-function assays showed that LARP4B promotes stemness, proliferation, metastasis, and angiogenesis in vitro and in vivo. Furthermore, LARP4B inhibition enhances the antitumor effects of sorafenib and blocks the metastasis-enhancing effects of low sorafenib concentrations in HCC. Mechanistically, LARP4B expression is upregulated by METTL3-mediated N-methyladenosine (m6A)-IGF2BP3-dependent modification in HCC. RNA- and RNA immunoprecipitation (RIP)- sequencing uncovered that LARP4B upregulates SPINK1 by binding to SPINK1 mRNA via the La motif and maintaining mRNA stability. LARP4B activates the SPINK1-mediated EGFR signaling pathway, which supports stemness, progression and sorafenib resistance in HCC. Additionally, a positive feedback loop with the LARP4B/SPINK1/p-AKT/C/EBP-β axis is responsible for the sorafenib-therapeutic benefit of LARP4B depletion. Overall, this study demonstrated that LARP4B facilitates HCC progression, and LARP4B inhibition provides benefits to sorafenib treatment in HCC, suggesting that LARP4B might be a potential therapeutic target for HCC.

摘要

La相关蛋白（LARP）通过与RNA结合来调节基因表达，并对包括肿瘤在内的疾病进展具有关键作用。然而，LARP4B在肝细胞癌（HCC）进展中的作用及其潜在机制仍不清楚。在本研究中，我们发现LARP4B表达上调，且与HCC患者的不良预后相关。功能获得和功能缺失实验表明，LARP4B在体外和体内均可促进干性、增殖、转移和血管生成。此外，抑制LARP4B可增强索拉非尼的抗肿瘤作用，并阻断低浓度索拉非尼在HCC中增强转移的作用。机制上，在HCC中，LARP4B的表达通过METTL3介导的N6-甲基腺苷（m6A）-IGF2BP3依赖性修饰而上调。RNA和RNA免疫沉淀（RIP）测序发现，LARP4B通过La模体与SPINK1 mRNA结合并维持mRNA稳定性，从而上调SPINK1。LARP4B激活SPINK1介导的EGFR信号通路，该通路支持HCC的干性、进展和索拉非尼耐药性。此外，LARP4B/SPINK1/p-AKT/C/EBP-β轴的正反馈环是LARP4B缺失对索拉非尼治疗有益的原因。总体而言，本研究表明LARP4B促进HCC进展，抑制LARP4B对HCC的索拉非尼治疗有益，提示LARP4B可能是HCC的一个潜在治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/202c/11063073/5e3348c20a4d/41420_2024_1985_Fig8_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/202c/11063073/4311898b8b9f/41420_2024_1985_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/202c/11063073/5a2697c84d5c/41420_2024_1985_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/202c/11063073/7568e4f983cd/41420_2024_1985_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/202c/11063073/5e3348c20a4d/41420_2024_1985_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/202c/11063073/3ffb4003159f/41420_2024_1985_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/202c/11063073/b739c365dda0/41420_2024_1985_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/202c/11063073/c659e53bf93b/41420_2024_1985_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/202c/11063073/4401b2826aff/41420_2024_1985_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/202c/11063073/4311898b8b9f/41420_2024_1985_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/202c/11063073/5a2697c84d5c/41420_2024_1985_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/202c/11063073/7568e4f983cd/41420_2024_1985_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/202c/11063073/5e3348c20a4d/41420_2024_1985_Fig8_HTML.jpg

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本文引用的文献

1
Genetic alterations shaping tumor response to anti-EGFR therapies.导致肿瘤对抗 EGFR 治疗产生应答差异的遗传改变。
Drug Resist Updat. 2022 Sep;64:100863. doi: 10.1016/j.drup.2022.100863. Epub 2022 Aug 27.
2
Mechanism of cancer stemness maintenance in human liver cancer.肝癌中癌症干细胞干性维持的机制。
Cell Death Dis. 2022 Apr 21;13(4):394. doi: 10.1038/s41419-022-04848-z.
3
RNA-binding proteins in regulating mRNA stability and translation: roles and mechanisms in cancer.RNA 结合蛋白在调节 mRNA 稳定性和翻译中的作用及其在癌症中的机制。
环状异戊烯基半胱氨酸羧甲基转移酶上调并抑制膀胱癌的恶性行为。
Transl Oncol. 2025 Feb;52:102262. doi: 10.1016/j.tranon.2024.102262. Epub 2024 Dec 28.
4
Decreased lncRNA HNF4A-AS1 facilitates resistance to sorafenib-induced ferroptosis of hepatocellular carcinoma by reprogramming lipid metabolism.lncRNA HNF4A-AS1表达降低通过重编程脂质代谢促进肝癌对索拉非尼诱导的铁死亡的抗性。
Theranostics. 2024 Oct 21;14(18):7088-7110. doi: 10.7150/thno.99197. eCollection 2024.
Semin Cancer Biol. 2022 Nov;86(Pt 2):664-677. doi: 10.1016/j.semcancer.2022.03.025. Epub 2022 Apr 2.
4
Cancer stem cells in hepatocellular carcinoma - from origin to clinical implications.肝癌中的癌症干细胞——从起源到临床意义。
Nat Rev Gastroenterol Hepatol. 2022 Jan;19(1):26-44. doi: 10.1038/s41575-021-00508-3. Epub 2021 Sep 9.
5
EGFR activation limits the response of liver cancer to lenvatinib.表皮生长因子受体（EGFR）激活限制了肝癌对乐伐替尼的反应。
Nature. 2021 Jul;595(7869):730-734. doi: 10.1038/s41586-021-03741-7. Epub 2021 Jul 21.
6
DNMT1-mediated methylation of BEX1 regulates stemness and tumorigenicity in liver cancer.DNMT1 介导的 BEX1 甲基化调控肝癌干细胞特性和肿瘤发生。
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7
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