J Cancer 2018; 9(24):4642-4649. doi:10.7150/jca.27686

Research Paper

Hedgehog Interacting Protein 1 is a Prognostic Marker and Suppresses Cell Metastasis in Gastric Cancer

Hui Sun1,2,3*, Shu juan Ni1,2,3*, Min Ye1,2,3, Weiwei Weng1,2,3, Qiongyan Zhang1,2,3, Meng Zhang1,2,3, Cong Tan1,2,3, Lei Wang1,2,3, Dan Huang1,2,3, Xiang Du1,2,3, Midie Xu1,2,3✉, Weiqi Sheng1,2,3✉

1. Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
2. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
3. Institute of Pathology, Fudan University, Shanghai 200032, China
* These authors contributed equally to this work.

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Sun H, Ni Sj, Ye M, Weng W, Zhang Q, Zhang M, Tan C, Wang L, Huang D, Du X, Xu M, Sheng W. Hedgehog Interacting Protein 1 is a Prognostic Marker and Suppresses Cell Metastasis in Gastric Cancer. J Cancer 2018; 9(24):4642-4649. doi:10.7150/jca.27686. Available from http://www.jcancer.org/v09p4642.htm

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Background: 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.

Methods: 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.

Results: 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).

Conclusion: HHIP may be a promising tumor metastatic-suppressor and prognostic biomarker for gastric cancer.

Keywords: gastric cancer, HHIP, expression, metastasis, survival