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Linc-KILH 通过抑制 KRT19 磷酸化增强 Notch1 信号通路并促进肝癌的恶性进展。

Linc-KILH potentiates Notch1 signaling through inhibiting KRT19 phosphorylation and promotes the malignancy of hepatocellular carcinoma.

机构信息

The Affiliated Changzhou NO.2 People's Hospital of Nanjing Medical University, 29 XingLongXiang Road, Changzhou, Jiangsu 213000, P.R. China.

School of medicine, Southeast University, Nanjing, China.

出版信息

Int J Biol Sci. 2021 Feb 8;17(3):768-780. doi: 10.7150/ijbs.52279. eCollection 2021.

DOI:10.7150/ijbs.52279
PMID:33767587
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7975697/
Abstract

Long noncoding RNAs (LncRNAs) are emerging as crucial regulators in the pathophysiological process of various tumors, including HCC. Here, we identify a novel lncRNA Linc-KILH (KRT19 interacting long noncoding RNA in hepatocellular carcinoma), which is significantly up-regulated in HCC tissues and positively correlated with larger tumor size, severer microvascular invasion, more intrahepatic metastasis and decreased survival of HCC patients. Silence of Linc-KILH remarkably inhibited the proliferation and metastasis abilities of KRT19-positive HCC cells and . Mechanistically, Linc-KILH interacts with KRT19 and then inhibits the phosphorylation of KRT19 on Ser35, thereby, enhancing the translocation of KRT19 from cytoplasm to membrane in KRT19 positive HCC cells. Additionally, we validated that KRT19 interacts with β-catenin but not RAC1 in HCC cells. Linc-KILH enhanced the interaction between β-catenin and KRT19 in cytoplasm and promoted the nuclear translocation of β-catenin in HCC cells. Furthermore, Linc-KILH could enhance the promoting function of KRT19 on Notch1 signaling with the existence of KRT19 in HCC cells. Collectively, we revealed that Linc-KILH exerts a vital function in KRT19 positive HCC progression and may likely be developed into an effective therapeutic target for HCC.

摘要

长链非编码 RNA（lncRNA）在各种肿瘤的病理生理过程中，包括 HCC 中，作为重要的调控因子而崭露头角。在这里，我们鉴定了一种新型的 lncRNA Linc-KILH（肝癌中与 KRT19 相互作用的长非编码 RNA），它在 HCC 组织中显著上调，并与肿瘤体积较大、微血管侵犯较重、肝内转移较多和 HCC 患者生存时间缩短呈正相关。沉默 Linc-KILH 显著抑制了 KRT19 阳性 HCC 细胞的增殖和转移能力。机制上，Linc-KILH 与 KRT19 相互作用，然后抑制 KRT19 在 Ser35 上的磷酸化，从而增强 KRT19 在 KRT19 阳性 HCC 细胞中的细胞质到膜的易位。此外，我们验证了 KRT19 在 HCC 细胞中与 β-连环蛋白相互作用，而不是与 RAC1 相互作用。Linc-KILH 增强了细胞质中 β-连环蛋白与 KRT19 的相互作用，并促进了 HCC 细胞中 β-连环蛋白的核易位。此外，Linc-KILH 可以增强 KRT19 在 HCC 细胞中对 Notch1 信号的促进作用。总之，我们揭示了 Linc-KILH 在 KRT19 阳性 HCC 进展中发挥着重要作用，并且可能成为 HCC 的有效治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21e3/7975697/664948b63fc4/ijbsv17p0768g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21e3/7975697/11c339ac2f2d/ijbsv17p0768g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21e3/7975697/ec80c5696fb8/ijbsv17p0768g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21e3/7975697/8141b7af5d76/ijbsv17p0768g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21e3/7975697/4cee1baa2c16/ijbsv17p0768g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21e3/7975697/e10f9b92cdad/ijbsv17p0768g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21e3/7975697/664948b63fc4/ijbsv17p0768g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21e3/7975697/11c339ac2f2d/ijbsv17p0768g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21e3/7975697/5e016a5c0a49/ijbsv17p0768g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21e3/7975697/ec80c5696fb8/ijbsv17p0768g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21e3/7975697/8141b7af5d76/ijbsv17p0768g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21e3/7975697/4cee1baa2c16/ijbsv17p0768g005.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21e3/7975697/664948b63fc4/ijbsv17p0768g007.jpg

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