GASTROENTEROLOGY / EXPERIMENTAL RESEARCH
 
KEYWORDS
TOPICS
ABSTRACT
Introduction:
The ITGB6 gene encoding a protein that can regulate the integrin v6 heterodimer protein expression in different status was shown to play an important role in multiple human cancers, such as brain cancer, colon cancer and oral cancer, and is related to clinical progression. This study aims to explore the function and the mechanism of the ITGB6 gene or protein in pancreatic cancer.

Material and methods:
We examined the expression of ITGB6 in pancreatic cancer using immunohistochemistry and analyzed the relationship between the expression of ITGB6 and the clinicopathologic features in pancreatic cancer patients. In addition, a bioinformatic method was used to analyze the ITGB6 mRNA level in pancreatic tumor tissues compared with normal pancreatic tissues and to analyze the correlation between high KIF23 expression and prognosis in pancreatic cancer patients. Moreover, colony formation assay, MTT assay, cell scratch, cell invasion and western blot assays in vitro and a xenograft mouse model in vivo were performed to analyze the effect of KIF23 on proliferation and invasion of pancreatic cancer cells.

Results:
Increased expression of ITGB6 was significantly correlated with poor clinical outcome in both our clinical data and TCGA data of pancreatic cancer. Furthermore, functional assays revealed that ITGB6 knockdown in vivo and in vitro might inhibit cancer cell proliferation and the ability of invasion or migration.

Conclusions:
Our data suggest that ITGB6 is associated with pancreatic cancer malignant progression. Hence, ITGB6 may serve as a potential target of pancreatic cancer for future research, and further study is needed.

 
REFERENCES (39)
1.
Rahib L, Smith BD, Aizenberg R, et al. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Research 2014; 74: 2913.
 
2.
Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin 2015; 65: 87-108.
 
3.
Hidalgo M. Pancreatic cancer. N Engl J Med 2010; 362: 1605-17.
 
4.
Chan A, Diamandis EP, Blasutig IM. Strategies for discovering novel pancreatic cancer biomarkers. J Proteomics 2013; 81: 126-34.
 
5.
Yachida S, Jones S, Bozic I, et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 2010; 467: 1114-7.
 
6.
Kamisawa T, Wood LD, Itoi T, Takaori K. Pancreatic cancer. Lancet 2016; 388: 73-85.
 
7.
Hartwig W, Werner J, Jager D, Debus J, Buchler MW. Improvement of surgical results for pancreatic cancer. Lancet Oncol 2013; 14: e476-85.
 
8.
Stark A, Donahue TR, Reber HA, Hines OJ. Pancreatic cyst disease: a review. JAMA 2016; 315: 1882-93.
 
9.
Barczyk M, Carracedo S, Gullberg D. Integrins. Cell Tissue Res 2009; 339: 269-80.
 
10.
Johnson MS, Lu N, Denessiouk K, Heino J, Gullberg D. Integrins during evolution: evolutionary trees and model organisms. Biochim Biophys Acta 2009; 1788: 779-89.
 
11.
Ganguly KK, Pal S, Moulik S, Chatterjee A. Integrins and metastasis. Cell Adh Migr 2013; 7: 251-61.
 
12.
Hynes RO. Integrins: bidirectional, allosteric signaling machines. Cell 2002; 110: 673-87.
 
13.
Krissansen GW, Yuan Q, Jenkins D, et al. Chromosomal locations of the genes coding for the integrin beta 6 and beta 7 subunits. Immunogenetics 1992; 35: 58-61.
 
14.
Fernandez-Ruiz E, Sanchez-Madrid F. Regional localization of the human integrin beta 6 gene (ITGB6) to chromosome 2q24-q31. Genomics 1994; 21: 638-40.
 
15.
Campbell ID, Humphries MJ. Integrin structure, activation, and interactions. Cold Spring Harb Perspect Biol 2011; 3: a004994.
 
16.
Thomas GJ, Nyström ML, Marshall JF. Alphavbeta6 integrin in wound healing and cancer of the oral cavity. J Oral Pathol Med 2006; 35: 1-10.
 
17.
Breuss JM, Gallo J, Delisser HM, et al. Expression of the beta 6 integrin subunit in development, neoplasia and tissue repair suggests a role in epithelial remodeling. J Cell Sci 1995; 108: 2241-51.
 
18.
Bandyopadhyay A, Raghavan S. Defining the role of integrin alphavbeta6 in cancer. Curr Drug Targets 2009; 10: 645-52.
 
19.
Munger JS, Sheppard D. Cross Talk among TGF- signaling pathways, integrins, and the extracellular matrix. Cold Spring Harb Perspect Biol 2011; 3: a005017.
 
20.
Ghannad F, Nica D, Fulle MI, et al. Absence of v6 integrin is linked to initiation and progression of periodontal disease. Am J Pathol 2008; 172: 1271.
 
21.
Li HX, Zheng JH, Fan HX, et al. Expression of alphavbeta6 integrin and collagen fibre in oral squamous cell carcinoma: association with clinical outcomes and prognostic implications. J Oral Pathol Med 2013; 42: 547-56.
 
22.
Vogetseder A, Thies S, Ingold B, et al. v-Integrin isoform expression in primary human tumors and brain metastases. Int J Cancer 2013; 133: 2362-71.
 
23.
Bates RC, Bellovin DI, Brown C, et al. Transcriptional activation of integrin 6 during the epithelial-mesenchymal transition defines a novel prognostic indicator of aggressive colon carcinoma. J Clin Invest 2005; 115: 339-47.
 
24.
Niu J, Li Z. The roles of integrin v6 in cancer. Cancer Lett 2017; 403: 128-37.
 
25.
Zheng C, Zhou Y, Huang C, Zhang Z, Liu YI, Xu Y. Establishment of a rat autogenous arteriovenous fistula model following 5/6 nephrectomy. Exp Ther Med 2015; 10: 219-24.
 
26.
Elayadi AN, Samli KN, Prudkin L, et al. A peptide selected by biopanning identifies the integrin alphavbeta6 as a prognostic biomarker for nonsmall cell lung cancer. Cancer Res 2007; 67: 5889-95.
 
27.
Hazelbag S, Kenter GG, Gorter A, et al. Overexpression of the alpha v beta 6 integrin in cervical squamous cell carcinoma is a prognostic factor for decreased survival. J Pathol 2007; 212: 316-24.
 
28.
Desai K, Nair MG, Prabhu JS, et al. High expression of integrin 6 in association with the Rho–Rac pathway identifies a poor prognostic subgroup within HER2 amplified breast cancers. Cancer Med 2016; 5: 2000-11.
 
29.
Eberlein C, Kendrew J, Mcdaid K, et al. A human monoclonal antibody 264RAD targeting v6 integrin reduces tumour growth and metastasis, and modulates key biomarkers in vivo. Oncogene 2013; 32: 4406-16.
 
30.
Van Aarsen LA, Leone DR, Ho S, et al. Antibody-mediated blockade of integrin alpha v beta 6 inhibits tumor progression in vivo by a transforming growth factor-beta-regulated mechanism. Cancer Res 2008; 68: 561.
 
31.
Ahmed N, Riley C, Rice GE, Quinn MA, Baker MS. Alpha(v)beta(6) integrin-A marker for the malignant potential of epithelial ovarian cancer. J Histochem Cytochem 2002; 50: 1371-80.
 
32.
Morris DG, Huang X, Kaminski N, et al. Loss of integrin v6-mediated TGF- activation causes Mmp12-dependent emphysema. Nature 2003; 422: 169-73.
 
33.
Moore KM, Thomas GJ, Duffy SW, et al. Therapeutic targeting of integrin v6 in breast cancer. J Natl Cancer Inst 2014; 106: dju169.
 
34.
Whilding LM, Parentepereira AC, Zabinski T, et al. Targeting of aberrant v6 integrin expression in solid tumors using chimeric antigen receptor-engineered T cells. Mol Ther 2017; 25: 259-73.
 
35.
Nisic F, Jovanovic N, Mavija M, et al. Vitreous concentrations of vascular endothelial growth factor as a potential biomarker for postoperative complications following pars plana vitrectomy. Arch Med Sci 2019; 15: 449-56.
 
36.
Zhang X, Li H, Kou W, et al. Increased plasma microfibrillar-associated protein 4 is associated with atrial fibrillation and more advanced left atrial remodelling. Arch Med Sci 2019; 15: 632-40.
 
37.
Michalska-Kasiczak M, Bielecka-Dabrowa A, von Haehling S, Anker SD, Rysz J, Banach M. Biomarkers, myocardial fibrosis and co-morbidities in heart failure with preserved ejection fraction: an overview. Arch Med Sci 2018; 14: 890-909.
 
38.
Patoulias DI. Is miRNA-375 a promising biomarker for early detection and monitoring of patients with type 2 diabetes? Arch Med Sci Atheroscler Dis 2018; 3: e119-22.
 
39.
Sidiropoulou T, Karaferi A, Stachtos G, et al. Propofol but not sevoflurane decreases circulating levels of sEGFR and sE-selectin after colorectal cancer surgery. Arch Med Sci Civil Dis 2019; 4: e41-e50.
 
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