Sun Hui, Ni Shu Juan, Ye Min, Weng Weiwei, Zhang Qiongyan, Zhang Meng, Tan Cong, Wang Lei, Huang Dan, Du Xiang, Xu Midie, Sheng Weiqi
Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
J Cancer. 2018 Nov 24;9(24):4642-4649. doi: 10.7150/jca.27686. eCollection 2018.
: The gene Hedgehog interacting protein (HHIP) is a pivotal morphogen for multiple developmental processes. However, the expression and clinical correlation of HHIP in gastric cancer (GC) has not been fully investigated. Here, we aimed to explore the expression of HHIP in gastric cancer (GC) and evaluate its clinicopathological and functional correlations. : The expression of HHIP mRNA was first determined in the Human Protein Atlas (HPA) and The Cancer Genome Atlas (TCGA) GC database and then validated by RT-qPCR (n = 41) and immunohistochemistry (IHC, n = 95) in a cohort of in-house GC patients and in 29 cases of gastric intraepithelial neoplasia (GIN). The clinicopathological and functional relationship of HHIP with GC were also analyzed. : We found that HHIP mRNA were significantly downregulated in GC in the TCGA and HPA databases, as well as in our in-house cohort (P < 0.05). HHIP mRNA is mainly located in the cell nucleus, while HHIP protein is mainly located in the cell cytoplasm. Moreover, the HHIP protein level in the GIN tissues was significantly higher than that in the GC tissues (P < 0.001) and significantly lower than that in adjacent normal controls (P < 0.001). In addition, low HHIP expression was correlated with lymphatic metastasis (P = 0.041), pTNM stage (P = 0.007) and nervous system invasion (P = 0.001). Furthermore, we observed strong positive correlations between HHIP protein expression and overall survival (P < 0.001) and disease-free survival (P = 0.027) in GC patients. HHIP protein expression was an independent prognostic factor for overall survival (P < 0.001). Functional experimental results showed that overexpression of HHIP attenuated the migration and invasion ability of GC cells (P < 0.01). : HHIP may be a promising tumor metastatic-suppressor and prognostic biomarker for gastric cancer.
刺猬蛋白相互作用蛋白（HHIP）基因是多种发育过程中的关键形态发生素。然而，HHIP在胃癌（GC）中的表达及临床相关性尚未得到充分研究。在此，我们旨在探讨HHIP在胃癌（GC）中的表达，并评估其临床病理及功能相关性。：首先在人类蛋白质图谱（HPA）和癌症基因组图谱（TCGA）胃癌数据库中确定HHIP mRNA的表达，然后通过实时定量聚合酶链反应（RT-qPCR，n = 41）和免疫组织化学（IHC，n = 95）在一组内部胃癌患者及29例胃上皮内瘤变（GIN）病例中进行验证。还分析了HHIP与胃癌的临床病理及功能关系。：我们发现，在TCGA和HPA数据库以及我们的内部队列中，胃癌中HHIP mRNA均显著下调（P < 0.05）。HHIP mRNA主要位于细胞核中，而HHIP蛋白主要位于细胞质中。此外，GIN组织中的HHIP蛋白水平显著高于胃癌组织（P < 0.001），且显著低于相邻正常对照（P < 0.001）。此外，HHIP低表达与淋巴转移（P = 0.041）、pTNM分期（P = 0.007）及神经侵犯（P = 0.001）相关。此外，我们观察到胃癌患者中HHIP蛋白表达与总生存期（P < 0.001）和无病生存期（P = 0.027）之间存在强正相关。HHIP蛋白表达是总生存期的独立预后因素（P < 0.001）。功能实验结果表明，HHIP过表达减弱了胃癌细胞的迁移和侵袭能力（P < 0.01）。：HHIP可能是一种有前景的胃癌肿瘤转移抑制因子和预后生物标志物。
