title: Serine Protease Inhibitor Kazal Type 1 (SPINK1) Promotes Proliferation of Colorectal Cancer Through the Epidermal Growth Factor as a Prognostic Marker.
abstract: Serine protease inhibitor Kazal type-1 (SPINK1), a trypsin kinase inhibitor, is involved in inflammation, cell proliferation and carcinogenesis. The role and association between SPINK1, EGFR and Ki-67 in colorectal adenoma (CRA) and colorectal cancer (CRC) are still unknown. In this study, we used immunohistochemical stain to evaluate expression of SPINK1, EGFR and Ki-67 proteins in 30 CRA and 53 CRC patients semiquantitatively, and then analyzed their correlation with clinicopathologic parameters. Our results revealed that SPINK1 expression was noted in the upper and basal parts of the crypts in CRA and was more intensely related with cellular atypia. EGFR expression was found in 13 out of 30 adenomas, including 9 out of 15 adenomas with dysplasia or synchronous CRC (60 %), and 4 out of 15 adenomas without dysplasia (26.7 %). In CRC, high SPINK1 expression was significantly associated with males (p = 0.041) and advanced disease stage (p = 0.015). EGFR positivity was significantly correlated with higher T stage (p = 0.004) and disease stage (stage I-IV, p = 0.017; early vs. late, p = 0.015). Pearson's correlation showed positive correlation between the SPINK1 intensity and EGFR immunoreactivity (p = 0.011), and Ki-67 and SPINK1 intensity or percentage (p = 0.017 and p = 0.039 respectively). In Kaplan-Meier analyses, patients with high SPINK1 intensity tended to have shorter overall survival (p = 0.03). Concomitant expression of high SPINK1 intensity and EGFR was also identified as being associated with poor prognosis (p = 0.015). In conclusion, high SPINK1 expression is associated with advanced stage and poor prognosis. There is positive correlation between high SPINK1 expression, EGFR immunoreactivity, and high Ki-67 labeling index. The SPINK1 protein seems to play a role in tumor proliferation and malignant transformation through the EGFR pathway. SPINK1 may serve as a prognostic biomarker in therapeutic targeting in the future.
authors.affiliation: Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, No. 100, Tzyou 1st Road, Kaohsiung, 807, Taiwan.
authors.forename: Yi-Ting
authors.initials: YT
authors.lastname: Chen
authors.forename: Shu-Chuan
authors.initials: SC
authors.lastname: Tsao
authors.forename: Shyng-Shiou F
authors.initials: SS
authors.lastname: Yuan
authors.forename: Hung-Pei
authors.initials: HP
authors.lastname: Tsai
authors.forename: Chee-Yin
authors.initials: CY
authors.lastname: Chai
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology*; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D019394:Ki-67 Antigen / Q000235:genetics; D008297:Male; D011379:Prognosis; D015398:Signal Transduction / Q000235:genetics; D014359:Trypsin Inhibitor, Kazal Pancreatic
chemical_list: D014408:Biomarkers, Tumor; D002352:Carrier Proteins; D019394:Ki-67 Antigen; C486642:SPINK1 protein, human; D014359:Trypsin Inhibitor, Kazal Pancreatic; C512478:EGFR protein, human; D066246:ErbB Receptors