LINC01468 drives NAFLD-HCC progression through CUL4A-linked degradation of SHIP2.
LINC01468 drives NAFLD-HCC progression through CUL4A-linked degradation of SHIP2.
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LINC01468 通过 CUL4A 相关的 SHIP2 降解驱动 NAFLD-HCC 进展
DOI：
10.1038/s41420-022-01234-8
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发表时间：
2022-11-07
影响因子：
7
通讯作者：
Tang, Bo
中科院分区：
文献类型：
--
作者：
Wang, Hongquan;Wang, Yan;Lai, Shihui;Zhao, Liang;Liu, Wenhui;Liu, Shiqian;Chen, Haiqiang;Wang, Jinhua;Du, Guanhua;Tang, Bo
越来越多的证据表明，长非编码RNA(LncRNAs)在肝细胞癌中被解除调控，并在非酒精性脂肪性肝病(NAFLD)的发病机制中发挥作用。然而，目前对lncRNAs在NAFLD相关肝细胞癌中的作用的了解是有限的。在这项研究中，对来自NAFLD驱动的肝细胞癌患者的三对人肝样本及其邻近样本的转录图谱分析显示，LINC01468的表达显著上调。体外和体内功能获得和丧失实验表明，LINC01468通过脂肪生成促进了肝癌细胞的增殖。在机制上，LINC01468结合SHIP2，促进CUL4A(cullin 4 A，CUL4A)连接的泛素降解，从而激活PI3K/AKT/mTOR信号通路，促进从头合成脂质，促进肝细胞癌进展。重要的是，SHIP2抑制剂逆转了LINC01468过表达诱导的索拉非尼耐药性。此外，ALKBH5介导的N6-甲基腺苷(M6A)修饰导致LINC01468 RNA稳定和上调。综上所述，这些发现表明了一种新的机制，即LINC01468介导的脂肪生成通过CUL4A连接的SHIP2降解促进肝癌进展。LINC01468作为非酒精性脂肪性肝病肝细胞癌进展的驱动因素，突出了LINC01468-SHIP2轴作为肝细胞癌治疗靶点的潜力。
Accumulating evidence suggests that long noncoding RNAs (lncRNAs) are deregulated in hepatocellular carcinoma (HCC) and play a role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, the current understanding of the role of lncRNAs in NAFLD-associated HCC is limited. In this study, transcriptomic profiling analysis of three paired human liver samples from patients with NAFLD-driven HCC and adjacent samples showed that LINC01468 expression was significantly upregulated. In vitro and in vivo gain- and loss-of-function experiments showed that LINC01468 promotes the proliferation of HCC cells through lipogenesis. Mechanistically, LINC01468 binds SHIP2 and promotes cullin 4 A (CUL4A)-linked ubiquitin degradation, thereby activating the PI3K/AKT/mTOR signaling pathway, resulting in the promotion of de novo lipid biosynthesis and HCC progression. Importantly, the SHIP2 inhibitor reversed the sorafenib resistance induced by LINC01468 overexpression. Moreover, ALKBH5-mediated N6-methyladenosine (m6A) modification led to stabilization and upregulation of LINC01468 RNA. Taken together, the findings indicated a novel mechanism by which LINC01468-mediated lipogenesis promotes HCC progression through CUL4A-linked degradation of SHIP2. LINC01468 acts as a driver of HCC progression from NAFLD, highlights the potential of the LINC01468-SHIP2 axis as a therapeutic target for HCC.
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影响因子：
4
作者：
Edimo, William's Elong;Ghosh, Somadri;Erneux, Christophe
通讯作者：
Erneux, Christophe
影响因子：
16.6
作者：
Bricambert J;Alves-Guerra MC;Esteves P;Prip-Buus C;Bertrand-Michel J;Guillou H;Chang CJ;Vander Wal MN;Canonne-Hergaux F;Mathurin P;Raverdy V;Pattou F;Girard J;Postic C;Dentin R
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Dentin R
DOI：
10.1002/path.5871
发表时间：
2022-05
期刊：
The Journal of pathology
影响因子：
--
作者：
通讯作者：
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影响因子：
5.2
作者：
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通讯作者：
Her GM
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影响因子：
37.3
作者：
Liu X;Liang Y;Song R;Yang G;Han J;Lan Y;Pan S;Zhu M;Liu Y;Wang Y;Meng F;Cui Y;Wang J;Zhang B;Song X;Lu Z;Zheng T;Liu L
通讯作者：
Liu L