SFRP4 expression correlates with epithelial mesenchymal transition-linked genes and poor overall survival in colon cancer patients.

BACKGROUND: Colon cancer is among the most commonly diagnosed cancers in the United States with an estimated 97220 new cases expected by the end of 2018. It affects 1.2 million people around the world and is responsible for about 0.6 million deaths every year. Despite decline in overall incidence and mortality over the past 30 years, there continues to be an alarming rise in early-onset colon cancer cases (< 50 years). Patients are often diagnosed at late stages of the disease and tend to have poor survival. We previously showed that the WNT "gatekeeper" gene, secreted frizzled-related protein 4 (SFRP4), is over-expressed in early-onset colon cancer. SFRP4 is speculated to play an essential role in cancer by inhibiting the epithelial mesenchymal transition (EMT). AIM: To investigate the correlation between SFRP4 expression and EMT-linked genes in colon cancer and how it affects patient survival. METHODS: SFRP4 expression relative to that of EMT-linked genes and survival analysis were performed using the University of California Santa Cruz Cancer Browser interface. RESULTS: SFRP4 was found to be co-expressed with the EMT-linked markers CDH2, FN1, VIM, TWIST1, TWIST2, SNAI1, SNAI2, ZEB1, ZEB2, POSTN, MMP2, MMP7, MMP9, and COL1A1. SFRP4 expression negatively correlated with the EMT-linked suppressors CLDN4, CLDN7, TJP3, MUC1, and CDH1. The expression of SFRP4 and the EMT-linked markers was higher in mesenchymal-like samples compared to epithelial-like samples which potentially implicates SFRP4-EMT mechanism in colon cancer. Additionally, patients overexpressing SFRP4 presented with poor overall survival (P = 0.0293). CONCLUSION: Considering the implication of SFRP4 in early-onset colon cancer, particularly in the context of EMT, tumor metastasis, and invasion, and the effect of increased expression on colon cancer patient survival, SFRP4 might be a potential biomarker for early-onset colon cancer that could be targeted for diagnosis and/or disease therapy.

Increasing Incidence of Colon Cancer in the Young: Assessing the Tumor Biology.

BACKGROUND: The overall incidence of colon cancer (CC) is decreasing, but with increasing early-onset colon cancer (EOCC < 50 years old). Our recent study revealed unique overexpression of cartilage oligomeric matrix protein (COMP) in EOCC and its association with aggressiveness. The aim of this study was to assess CC biology, especially in the young, by evaluating the role of COMP in CC carcinogenesis and cancer progression, detecting COMP in serum and its association with disease stage. STUDY DESIGN: Cancer and matching noninvolved tissue blocks from 12 sporadic EOCC and late-onset colon cancer (LOCC) patients of 4 disease stages were obtained from pathology archives. Ribonucleic acid expression profiling of 770 cancer-related genes using nCounter platform was performed. The COMP levels from 16 EOCC and LOCC serum samples were measured by ELISA. Carcinoembryonic antigen levels from these 16 samples were taken at the time of diagnosis. Transwell assay was performed to elucidate the role of COMP in motility and metastases. RESULTS: Expression profiling revealed increased COMP levels in higher disease stage. There was 7-fold higher COMP expression (p ≤ 0.05) in stage III compare to stage I and its coexpression with GAS1, VEGFC, MAP3K8, SFRP1, and PRKACA. Higher COMP expression was seen in stage II compared with stage I (p = 0.07) and its coexpression withTLR2, IL8, RIN1, IRAK3, and CACNA2D2, and COMP was detectable in serum and showed significantly higher levels in EOCC compared with LOCC. Similar correlation was seen with CEA levels, but the difference was not significant. Transwell assay revealed significantly increased motility of HT-29 cells after treatment with recombinant COMP. CONCLUSIONS: These findings suggest different tumor biology between EOCC and LOCC. Cartilage oligomeric matrix protein plays a significant role in CC carcinogenesis and has potential as biomarker for CC, especially aggressive EOCC.

COMP Gene Coexpresses With EMT Genes and Is Associated With Poor Survival in Colon Cancer Patients.

BACKGROUND: About 1.2 million new cases of colon cancer (CC) and 0.6 million deaths are reported every year, establishing CC as an important contributor to worldwide cancer morbidity and mortality. Although the overall incidence and mortality of CC have declined over the past 3 decades, the number of early-onset colon cancer ([EOCC], patients <50 y old) continues to rise alarmingly. These young patients are often diagnosed at a more advanced stage and tend to have poor survival. Our recently published data showed that the cartilage oligomeric matrix protein (COMP) is overexpressed in early-onset colon cancer patients. COMP is also reported in several cancers to coexpress with epithelial-mesenchymal transition (EMT) transcription factors. Given the role of EMT in cancer metastasis and cell invasion, we assessed the correlation between COMP gene expression and EMT gene expression in CC, and COMP's relationship to patient survival. METHODS: mRNA expression of COMP was compared to that of EMT markers using the UCSC Cancer Genomics Browser. Survival analysis was performed using the UCSC Xena Browser for cancer genomics. RESULTS: Expression analysis revealed coexpression of COMP with the EMT markers CDH2, FN1, VIM, TWIST1, TWIST2, SNAI1, SNAI2, ZEB1, ZEB2, POSTN, MMP2, MMP9, and COL1A1. Samples that were more mesenchymal had higher expression levels of COMP and EMT markers, thus suggesting a potential role of COMP in EMT. Patients with increased COMP expression presented with poorer overall survival compared to patients with no change or reduced COMP expression (P = 0.02). CONCLUSIONS: These findings reveal COMP as a potential biomarker for CC especially in more aggressive CC and CC in young patients, with a likely role in EMT during tumor metastasis and invasion, and a contributing factor to patient survival.