Inhibition of TRPV4 remodels single cell polarity and suppresses the metastasis of hepatocellular carcinoma.
Inhibition of TRPV4 remodels single cell polarity and suppresses the metastasis of hepatocellular carcinoma.
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抑制TRPV4重塑单细胞极性并抑制肝细胞癌的转移。
DOI：
10.1038/s41419-023-05903-z
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发表时间：
2023-06-28
影响因子：
9
通讯作者：
Wei, Libin
中科院分区：
文献类型：
--
作者：
Liu, Jian;Guo, Yongjian;Zhang, Ruitian;Xu, Ye;Luo, Chengju;Wang, Rui;Xu, Shu;Wei, Libin
肝细胞癌（HCC）是一种恶性肿瘤，经常引起肝内和肝外转移。转移性肝癌患者的总体预后较差。最近，单细胞（sc）极性被证明是一些液相肿瘤细胞的固有特征，并直接参与细胞对血管的粘附和肿瘤转移。在这里，我们表征了悬浮培养中 HCC 细胞维持的 SC 极性，并研究了其在转移过程中的作用和调节机制。我们证明瞬时受体电位香草酸 4 (TRPV4) 是通过激活 Ca2+ 依赖性 AMPK/MLC/ERM 通路来促进 SC 极性的调节剂。这减弱了转移性肝癌细胞与血管内皮细胞的粘附。抑制TRPV4可以减少癌症转移，这不仅影响肿瘤细胞的迁移和侵袭，还可以防止与血管内皮细胞的粘附。此外，我们发现了一种名为 GL-V9 的全新 TRPV4 抑制剂，它可以改变 SC 极化程度并显着降低 HCC 细胞的转移能力。综上所述，我们的数据表明 TRPV4 和钙信号是转移性 HCC 中重要的 SC 极性调节剂，导致 HCC 细胞去极化的药物干预表明一种有前途的癌症转移治疗方法。
Hepatocellular carcinoma (HCC) is a malignant tumor, frequently causing both intrahepatic and extrahepatic metastases. The overall prognosis of patients with metastatic HCC is poor. Recently, single-cell (sc) polarity is proved to be an innate feature of some tumor cells in liquid phase, and directly involved in the cell adhesion to blood vessel and tumor metastasis. Here, we characterize the maintained sc polarity of HCC cells in a suspension culture, and investigate its roles and regulatory mechanisms during metastasis. We demonstrate that transient receptor potential vanilloid 4 (TRPV4) is a promoting regulator of sc polarity via activating Ca2+-dependent AMPK/MLC/ERM pathway. This attenuates the adhesion of metastatic HCC cells to vascular endothelial cells. The reduction of cancer metastases can result from TRPV4 inhibition, which not only impacts the migration and invasion of tumor cells, but also prevents the adhesion to vascular endothelial cells. Additionally, we discover a brand-new TRPV4 inhibitor called GL-V9 that modifies the degree of sc polarization and significantly decreases the metastatic capacity of HCC cells. Taken together, our data shows that TRPV4 and calcium signal are significant sc polarity regulators in metastatic HCC, and that the pharmacological intervention that results in HCC cells becoming depolarized suggests a promising treatment for cancer metastasis.
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影响因子：
5.6
作者：
Chinigò G;Fiorio Pla A;Gkika D
通讯作者：
Gkika D
影响因子：
8
作者：
Adapala RK;Thoppil RJ;Ghosh K;Cappelli HC;Dudley AC;Paruchuri S;Keshamouni V;Klagsbrun M;Meszaros JG;Chilian WM;Ingber DE;Thodeti CK
通讯作者：
Thodeti CK
DOI：
10.1097/ppo.0000000000000312
发表时间：
2018
期刊：
Cancer journal (Sudbury, Mass.)
影响因子：
--
作者：
Hope JM;Greenlee JD;King MR
通讯作者：
King MR
影响因子：
3.9
作者：
Gu Y;Yu J;Ding C;Zhou Y;Yang J;Yu W;Zhang X;Huang H
通讯作者：
Huang H
影响因子：
4.6
作者：
Alvarado-Estrada K;Marenco-Hillembrand L;Maharjan S;Mainardi VL;Zhang YS;Zarco N;Schiapparelli P;Guerrero-Cazares H;Sarabia-Estrada R;Quinones-Hinojosa A;Chaichana KL
通讯作者：
Chaichana KL