Hunan Provincial Key Laboratory of Hepatobiliary Disease Research, Division of Hepatobiliary & Pancreatic Surgery, Department of Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
Department of General Surgery, The 2nd Affiliated Hospital, Hunan University of Chinese Medicine, Changsha, Hunan 410005, China.
Biomed Pharmacother. 2018 May;101:910-919. doi: 10.1016/j.biopha.2018.03.014. Epub 2018 Mar 22.
TRPV4 (transient receptor potential vanilloid 4), a member of the TRP superfamily, has been reported to correlate with several different forms of cancers. However, the role of TRPV4 in human hepatocellular carcinoma (HCC) remains unclear. The present study demonstrated that elevated expression of TRPV4 was shown in HCC tumor tissues when compared with paired non-tumoral livers both in protein and mRNA levels. Furthermore, the enhanced expression of TRPV4 was highly associated with histological grade (P = 0.036) and the number of tumors (P = 0.045). Pharmacological inhibition of TRPV4 channels in HCC cells with the specific antagonist HC-067047 suppressed cell proliferation, induced apoptosis and decreased the migration capability by attenuating the epithelial-mesenchymal transition (EMT) process in vitro. The p-ERK expression was apparently repressed after treatment with the TRPV4 antagonist, further blockade of the ERK pathway with U0126 could significantly aggravate HCC cells apoptosis. In NOD-SCID mouse xenograft models, intraperitoneal injection of HC-067047 could obviously suppress tumor growth and induce apoptosis in vivo. Together, our studies showed that the antitumor effects caused by TRPV4 channel inhibition in HCC cell lines might be attributed to the suppression of EMT process and inactivation of p-ERK which induced subsequent cell apoptosis. Thus, pharmacological inhibition of TRPV4 channel may be an option for HCC treatment.
TRPV4（瞬时受体电位香草酸亚型 4）是 TRP 超家族的成员，据报道与多种不同形式的癌症相关。然而，TRPV4 在人肝细胞癌（HCC）中的作用尚不清楚。本研究表明，与配对的非肿瘤肝脏相比，TRPV4 在 HCC 肿瘤组织中的蛋白和 mRNA 水平均升高。此外，TRPV4 的高表达与组织学分级（P=0.036）和肿瘤数量高度相关（P=0.045）。用特异性拮抗剂 HC-067047 抑制 HCC 细胞中的 TRPV4 通道可抑制细胞增殖，诱导细胞凋亡，并通过减弱上皮-间充质转化（EMT）过程来降低迁移能力。用 TRPV4 拮抗剂处理后，p-ERK 的表达明显受到抑制，进一步用 U0126 阻断 ERK 通路可显著加重 HCC 细胞凋亡。在 NOD-SCID 小鼠异种移植模型中，腹腔注射 HC-067047 可明显抑制肿瘤生长并诱导体内细胞凋亡。总之，我们的研究表明，TRPV4 通道抑制在 HCC 细胞系中引起的抗肿瘤作用可能归因于 EMT 过程的抑制和 p-ERK 的失活，从而诱导随后的细胞凋亡。因此，TRPV4 通道的药理学抑制可能是 HCC 治疗的一种选择。
