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A Novel Tumor Suppressor SPINK5 Serves as an Independent Prognostic Predictor for Patients with Head and Neck Squamous Cell Carcinoma

Authors Lv Z, Wu K, Qin X, Yuan J, Yan M, Zhang J, Wang L, Ji T, Cao W, Chen W

Received 27 October 2019

Accepted for publication 25 April 2020

Published 23 June 2020 Volume 2020:12 Pages 4855—4869

DOI https://doi.org/10.2147/CMAR.S236266

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Editor who approved publication: Dr Eileen O'Reilly


Zhongjing Lv,1,2,* Kun Wu,1,3,* Xing Qin,1,3 Jian Yuan,2 Ming Yan,1,3 Jianjun Zhang,1,3 Lizhen Wang,1,4 Tong Ji,1,3 Wei Cao,1,3 Wantao Chen1,3

1Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Department of Stomatology, Affiliated Hospital of Xuzhou Medical University, Xuzhou City, Jiangsu Province, People’s Republic of China; 3Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of Stomatology, National Clinical Research Center of Stomatology, Shanghai, People’s Republic of China; 4Department of Oral Pathology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Wantao Chen; Wei Cao
Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Key Laboratory of Stomatology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
Email chenwantao2002@hotmail.com; caowei561521@hotmail.com

Background: In our previous study, serine protease inhibitor Kazal-type 5 (SPINK5), which encodes the product of serine protease inhibitor lymphoepithelial Kazal-type-related inhibitor (LEKTI) was found to be down-regulated in head and neck squamous cell carcinoma (HNSCC) using oligonucleotide microarrays. However, the function and clinical implications of SPINK5/LEKTI remain obscure in HNSCC.
Methods: The endogenous expression level of SPINK5/LEKTI was further verified in 9 HNSCC cell lines and HNSCCs by means of reverse transcription-polymerase chain reaction, real-time PCR, Western blotting and immunohistochemistry. The biological function of SPINK5/LEKTI was investigated in vitro and in vivo experiments. Kaplan–Meier survival analysis and Cox proportional hazards regression model were used to determine the correlation between SPINK5/LEKTI expression and clinical outcome.
Results: Down-regulation expression of SPINK5/LEKTI was found in six out of nine HNSCC cell lines and in 85.7% HNSCC specimens (P< 0.0001). Upon silencing of SPINK5/LEKTI, the cell proliferation, plate colony formation and cell invasion of WU-HN6 cells were significantly increased, while exogenous overexpression of SPINK5/LEKTI, the proliferation, plate colony and invasion of WU-HN13 and HN30 cells were remarkably inhibited with the arrest of G1 cell cycle (P=0.0001, P=0.003, respectively). HNSCC patients with lower LEKTI levels had significantly inferior overall survival compared to those patients with higher LEKTI (P=0.0017) by Kaplan–Meier survival analysis. Univariate and multivariate Cox proportional hazards regression model analysis revealed that LEKTI expression was an independent prognostic predictor for HNSCC patients (HR=0.114, 95% CI:0.044– 0.292, P< 0.001).
Conclusion: Our results demonstrate that SPINK5/LEKTI might be a tumor suppressor in HNSCCs and serve as an independent prognostic predictor for HNSCC patients.

Keywords: SPINK5/LEKTI, biological function, head and neck squamous cell carcinoma, prognostic predictor

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