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.

Serine protease inhibitor Kazal type 1 (SPINK1) as a prognostic marker in stage IV colon cancer patients receiving cetuximab based targeted therapy

“…Experiments performed using cultured tissue indicate that SPINK1 expression is associated with CRC tumour growth, and studies of CRC patients indicate that SPINK1 is associated with tumour size and metastasis 14 17. Our previous study in CRC cases also demonstrated that increased SPINK1 expression is associated with aggressive tumour behaviour, metastasis and reduced OS 12. Additional evidence shows that, by inducing autocrine formation and by disrupting the balance of cell matrix interactions, SPINK1 may enhance cancer invasiveness, metastasis and progression 7 14 18…”

“…As overexpression of EGFR contributes to carcinogenesis, including cancer cell proliferation, apoptosis, angiogenesis and metastasis, EGFR is associated with advanced stage and poor outcome 12 19. EGFR is also selected for targeted therapy as EGFR expression is elevated in 70–80% of CRC patients 20.…”

Emerging Roles of SPINK1 in Cancer

“…Increased serum SPINK1 has been found to be an independent prognostic factor in CRC (53 ). In some studies strong tissue staining for SPINK1 was found to be associated with adverse prognosis (52,54 ), but in another study strong expression correlated with good prognosis, especially if the tumor also showed positive EGFR staining (55 ). Interestingly, the recent study by Chen et al (54 ) showed a positive correlation between SPINK1 and EGFR, contradicting previously published results.…”

Overriding Elements in Colon Cancer Progression: Some Less Known Facts

“…SPINK1 and epidermal growth factor (EGF) bind to EGFR and stimulate proliferation via mitogenactivated protein kinases (MAPK) which was recorded in pancreatic adenocarcinoma. 24 In a study by Chen et al, 24 the SPINK1 protein played a role in tumor proliferation and malignant transformation in CRC through the EGFR pathway. SPINK1 was also used as a marker for predicting tumors in response to anti-EGFR treatment in CRC patients.…”