Association of Mixed Lineage Kinase Domain-Like Protein Expression With Prognosis in Patients With Colon Cancer

Abstract

Background: The mixed lineage kinase domain-like protein has recently been identified as a key downstream component of tumor necrosis factor-induced necroptosis, which is an important pathway of cancer cell death. The goal of the current study is to explore the expression of mixed lineage kinase domain-like protein in colon cancer tissues and evaluate the prognostic value in patients with colon cancer. Methods: We collected normal and cancer colon tissues from 135 patients diagnosed with colon cancer after radical operation during July 2007 to April 2009 at The Affiliated Hospital of Qingdao University. Immunohistochemistry analysis was scored using an established scoring system. Kaplan-Meier survival curves were generated for recurrence-free survival and overall survival for all patients and 2 subsets of patients. The relationship between mixed lineage kinase domain-like protein expression and prognosis parameter (recurrence-free survival, overall survival) was analyzed by univariate and multivariate Cox regression analyses. Results: The median age of all patients was 67 years and 56.3% were male. Low expression of mixed lineage kinase domain-like protein was associated with decreased overall survival (78.6 vs 81.2 months; P ¼ .011) in all patients. In the subset of 79 patients who received adjuvant chemotherapy, low expression of mixed lineage kinase domain-like protein was associated with decreased recurrence-free survival (60.4 vs 72.8 months; P ¼ .032) and decreased overall survival (66.3 vs 72.9 months; P ¼ .005). Low expression of mixed lineage kinase domain-like protein was associated with decreased overall survival (74.9 vs 79.8 months; P ¼ .006) and recurrence-free survival (69.6 vs 78.8 months; P ¼ .005) among patients with Tumor Node Metastasis (TNM) stage II colon cancer. Conclusions: Low expression of mixed lineage kinase domain-like protein was associated with decreased overall survival in all patient-group with resected colon cancer. It is associated with decreased recurrencefree survival and overall survival in the subset of patients who receive adjuvant chemotherapy and patients who were TNM stage II. Mixed lineage kinase domain-like protein may provide important prognostic information in patients with colon cancer.

Necroptotic cell death in anti‐cancer therapy

“…These findings suggest that RIPK3 is a critical tumor suppressor in intestinal inflammation and colitis‐associated colorectal cancer. Similarly, it has been shown that low levels of MLKL (Table ) are associated with decreased overall survival in patients with pancreatic adenocarcinoma, colon cancer and cervical squamous cell carcinoma . MLKL expression is involved in the modulation of local immunosurveillance of the tumor microenvironment (Figure ).…”

Necroptosis in Cholangiocarcinoma

“…As a consequence, a lower expression of necroptosis regulators seems to correlate with a worse prognosis in several types of carcinomas (i.e., breast, colorectal, gastric, and ovarian cancer, and head and neck and cervical squamous cell carcinoma), in acute myeloid leukemia, and in melanoma [30,[42][43][44][45][46][47][48]. However, the expression of RIPK1, RIPK3, and MLKL has been found to be upregulated in some cancers (i.e., glioblastoma, pancreatic, lung, and esophageal cancer), in which a high activation of the necroptotic cascade seems to be correlated with a poorer prognosis in different studies [6,36,41,[49][50][51][52][53]. The role of necroptosis in liver carcinogenesis is also still not clear.…”

Relevance of necroptosis in cancer

“…This indicates that RIPK3 expression may be negatively selected during the development or progression of breast and colorectal cancers. Likewise, reduced expression of MLKL was significantly associated with decreased overall survival of gastric, ovarian, cervix, colon and pancreatic cancers [35][36][37][38][39] (Table 1). Thus, MLKL expression could potentially serve as a prognostic biomarker for those cancers.…”