HHIP overexpression inhibits the proliferation, migration and invasion of non-small cell lung cancer

Autoři: Jian-Guo Zhao aff001;  Jian-Fang Wang aff001;  Jiang-Feng Feng aff001;  Xue-Ying Jin aff001;  Wan-Li Ye aff002
Působiště autorů: Department of Oncology, Shaoxing People's Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Shaoxing, Zhejiang, China aff001;  Department of Radiotherapy, Shaoxing People's Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Shaoxing, Zhejiang, China aff002
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: 10.1371/journal.pone.0225755



The primary purpose of this study is to investigate the effect of hedgehog-interacting protein (HHIP) overexpression on the proliferation, migration and invasion of non-small cell lung cancer (NSCLC).


Firstly, HHIP gene expression data of NSCLC tissues and normal tissues were obtained from GSE18842/GSE19804/GSE43458 databases of the Gene Expression Omnibus (GEO) database and then validated by TCGA NSCLC database in a cohort of 1027 cases of NSCLC patients and 108 cases of normal people. A chi-square test was used to analyze the relationship between HHIP expression and clinicopathological characteristics of NSCLC. The expression levels of HHIP in NSCLC cells were detected by quantitative-real time PCR. The function of HHIP was investigated by a series of in vitro assays. CCK-8, wounding healing, Transwell invasion assay were utilized to explore the mechanisms of HHIP.


HHIP mRNA were significantly down-regulated in NSCLC in three GEO databases and TCGA database (P<0.05). This result was confirmed in NSCLC cell lines by qRT-PCR analysis, its expression in normal NSCLC cell line BEAS-2B was significantly higher than that in NSCLC cells. Chi-square test results showed that the low expression of HHIP was correlated with gender, cancer type, TNM stage and tumor size. Functional experimental results showed that over-expressing HHIP significantly decreased the ability of cell proliferation, migration and invasion in NSCLC cells (P<0.05).


Overall, the above results indicated that HHIP could regulate proliferation, migration and invasion, and could be used as a judging criterion for identifying NSCLC classification and stage.

Klíčová slova:

Adenocarcinoma of the lung – Cancer cell migration – Gene expression – Hedgehog signaling – Lung and intrathoracic tumors – Malignant tumors – Non-small cell lung cancer – Secondary lung tumors


1. Wei S, Tian J, Song X, Wu B, Liu L. Causes of death and competing risk analysis of the associated factors for non-small cell lung cancer using the Surveillance, Epidemiology, and End Results database. Journal of cancer research and clinical oncology. 2018;144(1):145–55. Epub 2017/10/06. doi: 10.1007/s00432-017-2522-3 28980067.

2. Grabowski J, Glode A. Ramucirumab: A vascular endothelial growth factor receptor-2 inhibitor with activity in several malignancies. American journal of health-system pharmacy: AJHP: official journal of the American Society of Health-System Pharmacists. 2016;73(13):957–68. Epub 2016/05/25. doi: 10.2146/ajhp150188 27217518.

3. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA: a cancer journal for clinicians. 2018;68(1):7–30. Epub 2018/01/10. doi: 10.3322/caac.21442 29313949.

4. Bak M, Hansen C, Friis Henriksen K, Tommerup N. The human hedgehog-interacting protein gene: structure and chromosome mapping to 4q31.21—>q31.3. Cytogenetics and cell genetics. 2001;92(3–4):300–3. Epub 2001/07/04. doi: 10.1159/000056918 11435703.

5. Queiroz KC, Spek CA, Peppelenbosch MP. Targeting Hedgehog signaling and understanding refractory response to treatment with Hedgehog pathway inhibitors. Drug resistance updates: reviews and commentaries in antimicrobial and anticancer chemotherapy. 2012;15(4):211–22. Epub 2012/08/23. doi: 10.1016/j.drup.2012.05.002 22910179.

6. Cobourne MT, Green JB. Hedgehog signalling in development of the secondary palate. Frontiers of oral biology. 2012;16:52–9. Epub 2012/07/05. doi: 10.1159/000337543 22759669.

7. Buller NV, Rosekrans SL, Westerlund J, van den Brink GR. Hedgehog signaling and maintenance of homeostasis in the intestinal epithelium. Physiology (Bethesda, Md). 2012;27(3):148–55. Epub 2012/06/13. doi: 10.1152/physiol.00003.2012 22689790.

8. Lin EH, Kao YR, Lin CA, Kuo TY, Yang SP, Hsu CF, et al. Hedgehog pathway maintains cell survival under stress conditions, and drives drug resistance in lung adenocarcinoma. Oncotarget. 2016;7(17):24179–93. Epub 2016/03/26. doi: 10.18632/oncotarget.8253 27015549; PubMed Central PMCID: PMC5029693.

9. Zuo Y, Lv Y, Qian X, Wang S, Chen Z, Jiang Q, et al. Inhibition of HHIP Promoter Methylation Suppresses Human Gastric Cancer Cell Proliferation and Migration. Cellular physiology and biochemistry: international journal of experimental cellular physiology, biochemistry, and pharmacology. 2018;45(5):1840–50. Epub 2018/03/15. doi: 10.1159/000487875 29539620.

10. Sun H, Ni SJ, Ye M, Weng W, Zhang Q, Zhang M, et al. Hedgehog Interacting Protein 1 is a Prognostic Marker and Suppresses Cell Metastasis in Gastric Cancer. Journal of Cancer. 2018;9(24):4642–9. Epub 2018/12/28. doi: 10.7150/jca.27686 30588248; PubMed Central PMCID: PMC6299386.

11. Bian YH, Huang SH, Yang L, Ma XL, Xie JW, Zhang HW. Sonic hedgehog-Gli1 pathway in colorectal adenocarcinomas. World journal of gastroenterology. 2007;13(11):1659–65. Epub 2007/04/28. doi: 10.3748/wjg.v13.i11.1659 17461467; PubMed Central PMCID: PMC4146943.

12. Yang L, He J, Huang S, Zhang X, Bian Y, He N, et al. Activation of hedgehog signaling is not a frequent event in ovarian cancers. Molecular cancer. 2009;8:112. Epub 2009/12/01. doi: 10.1186/1476-4598-8-112 19943941; PubMed Central PMCID: PMC2787497.

13. Kayed H, Kleeff J, Esposito I, Giese T, Keleg S, Giese N, et al. Localization of the human hedgehog-interacting protein (Hip) in the normal and diseased pancreas. Molecular carcinogenesis. 2005;42(4):183–92. Epub 2005/03/09. doi: 10.1002/mc.20088 15754313.

14. Tada M, Kanai F, Tanaka Y, Tateishi K, Ohta M, Asaoka Y, et al. Down-regulation of hedgehog-interacting protein through genetic and epigenetic alterations in human hepatocellular carcinoma. Clinical cancer research: an official journal of the American Association for Cancer Research. 2008;14(12):3768–76. Epub 2008/06/19. doi: 10.1158/1078-0432.Ccr-07-1181 18559595.

15. Thatcher EJ, Patton JG. Small RNAs have a big impact on regeneration. RNA biology. 2010;7(3):333–8. Epub 2010/05/12. doi: 10.4161/rna.7.3.12085 20458186; PubMed Central PMCID: PMC4444050.

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2019 Číslo 11