Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an independent prognostic marker in wild-type KRAS metastatic colorectal cancer after colorectal liver metastasectomy.

Kuen-Feng Chen,Shung-Haur Yang,Chun-Chi Lin,Chueh-Chuan Yen,Jeng-Kai Jiang,Jen-Kou Lin,Hui-Chuan Yu,Wei-Shone Chen,Hao-Wei Teng,Hui-Mei Hsu,Wen-Ling Lin,Yuan-Tzu Lan

doi:10.1186/s12885-015-1300-3

Abstract

BackgroundThe impact of KRAS signaling on cancerous inhibitor of protein phosphatase 2A (CIP2A) expression has not yet been explored. We investigated the impact of KRAS on CIP2A expression in colorectal cancer patients after colorectal liver metastasectomy.MethodsWe examined CIP2A expression by immunohistochemistry (IHC) and used direct sequencing to identify the mutational status of KRAS exon 2 (codon 12 and 13). The association between CIP2A expression, KRAS genotype, clinicopathological parameters and survival were examined by the Kaplan–Meier method and the Cox proportional hazards model. A combination of immunoblotting and proliferation assays were employed to elucidate the role of CIP2A in signal transduction pathways in wild-type KRAS Caco-2 cells.ResultsA total of 220 colorectal cancer patients who had undergone colorectal liver metastasectomy were included in the study. The mutant KRAS genotype was associated with CIP2A overexpression. CIP2A expression was an independent prognostic marker in patients with wild-type KRAS metastatic colorectal cancer after colorectal liver metastasectomy (relative risk = 1.873, P = 0.019). Targeted silencing of CIP2A in Caco-2 cells (wild-type KRAS) led to decreased expression of pERK/ERK and decreased cell proliferation. Overexpression of mutant KRAS G12D in Caco-2 cells led to an increase in CIP2A expression and cell proliferation. In Caco-2 cells with the KRAS G12D, KRAS overexpression preserved the regulation effect of CIP2A in KRAS and abrogated the impact of CIP2A regulation on pERK/ERK and cell proliferation. CIP2A inhibition also increased the efficacy of cetuximab in Caco-2 cells.ConclusionsCIP2A is an independent prognostic marker in patients with wild-type KRAS metastatic colorectal cancer after colorectal liver metastasectomy.

Highlights

The impact of Kirsten Rat Sarcoma Viral Oncogene (KRAS) signaling on cancerous inhibitor of protein phosphatase 2A (CIP2A) expression has not yet been explored
We found that CIP2A only acts as an independent prognostic marker in patients with wild-type KRAS metastatic colorectal cancer after colorectal liver metastasectomy
Patient characteristics and association of clinical parameters with CIP2A expression A total of 220 patients who had undergone colorectal liver metastasectomy were enrolled in our study (Table 1)

Summary

Introduction

The impact of KRAS signaling on cancerous inhibitor of protein phosphatase 2A (CIP2A) expression has not yet been explored. We investigated the impact of KRAS on CIP2A expression in colorectal cancer patients after colorectal liver metastasectomy. The standard treatment for patients with colorectal liver metastasis is colorectal liver metastasectomy [2]; the rate of recurrence is Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a recently identified oncoprotein that is overexpressed in several malignancies, including leukemia, breast, gastric, prostate, lung, ovarian, head and neck carcinoma, and colorectal cancer [6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21]. It is well documented that EGFR signaling is the most important pathway in treating metastatic colorectal cancer [25,26]. The interplay between EGFR signaling and CIP2A in metastatic colorectal cancer warrants further investigation

Methods

Results

Conclusion