Song Yu, Tu Jianchen, Cheng Yanan, Zhou Fang, Liu Peilin, Zhou Shuangshuang, Gu Yongjun, Sun Yang
Department of Oncology, The First People Hospital of Zhangjiagang City, Soochow University, Zhangjiagang, China.
Department of Gastrointestinal Surgery, The First People Hospital of Zhangjiagang City, Soochow University, Zhangjiagang, China.
Front Oncol. 2020 Dec 22;10:1667. doi: 10.3389/fonc.2020.01667. eCollection 2020.
Human hedgehog-interacting protein (HHIP), a negative regulator of hedgehog (HH) signaling pathway, has been reported to be dysregulated in many types of cancer, including gastric cancer. However, the inhibitory role of HHIP as well as the underlying molecular mechanism of HHIP regulation in gastric cancer haven't been fully elucidated yet. In this study, we demonstrated that HHIP overexpression significantly suppressed the proliferation and invasion of AGS cells evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and transwell assays, respectively. Interestingly, methylation-specific polymerase chain reaction (MS-PCR, MSP) showed that HHIP overexpression dramatically decreased its promoter methylation levels in AGS cells. Furthermore, HHIP expression was higher in adjacent non-cancerous tissue compared to matched gastric cancer tissue. High HHIP level was negatively correlated with metastasis ( = 0.035) but not local recurrence ( = 0.58). Taken together, our study suggested that HHIP can modulate gastric cancer progression and metastasis via regulation of its promoter methylation levels in a feedback manner. Lower HHIP levels is positively associated with gastric cancer metastasis, which not only indicates HHIP could be served as a protective marker for gastric cancer, but also suggests restoring HHIP expression might be a potential therapeutic strategy for clinical treatment.
人刺猬因子相互作用蛋白（HHIP）是刺猬因子（HH）信号通路的负调节因子，据报道在包括胃癌在内的多种癌症中表达失调。然而，HHIP在胃癌中的抑制作用及其调控的潜在分子机制尚未完全阐明。在本研究中，我们分别通过3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐（MTT）和Transwell实验证明，HHIP过表达显著抑制了AGS细胞的增殖和侵袭。有趣的是，甲基化特异性聚合酶链反应（MS-PCR，MSP）显示，HHIP过表达显著降低了AGS细胞中其启动子的甲基化水平。此外，与配对的胃癌组织相比，HHIP在癌旁非癌组织中的表达更高。HHIP高表达与转移呈负相关（P = 0.035），但与局部复发无关（P = 0.58）。综上所述，我们的研究表明，HHIP可通过反馈调节其启动子甲基化水平来调控胃癌的进展和转移。较低的HHIP水平与胃癌转移呈正相关，这不仅表明HHIP可作为胃癌的一个保护性标志物，还提示恢复HHIP表达可能是一种潜在的临床治疗策略。
