P38γ Activation and BGP (Biliary Glycoprotein) Induction in Primates at Risk for Inflammatory Bowel Disease and Colorectal Cancer-A Comparative Study with Humans.

Harvinder Talwar,Benita Mcvicker,Martin Tobi

doi:10.3390/vaccines8040720

Abstract

Colorectal cancer (CRC) is a common cause of cancer-related deaths largely due to CRC liver metastasis (CRLM). Identification of targetable mechanisms continues and includes investigations into the role of inflammatory pathways. Of interest, MAPK is aberrantly expressed in CRC patients, yet the activation status is not defined. The present study assessed p38γ activation in CRC patients, cancer cells, and tissues of cotton top tamarin (CTT) and common marmoset (CM). The primate world is an overlooked resource as colitis-CRC-prone CTT are usually inure to liver metastasis while CM develop colitis but not CRC. The results demonstrate that p38γ protein and phosphorylation levels are significantly increased in CRC patients compared to normal subjects and CTT. Furthermore, p38γ phosphorylation is significantly elevated in human CRC cells and hepatoblastoma cells but not in CM colon. Additionally, carcinoembryonic antigen (CEA) and biliary glycoprotein (BGP) are induced in the CRC patients that showed p38γ phosphorylation. Inhibition of p38 MAPK in CRC cells showed a significant decline in cell growth with no effect on apoptosis or BGP level. Overall, p38γ is activated in CRC tumorigenesis and likely involves CEA antigens during CRLM in humans but not in the CTT or CM, that rarely develop CRLM.

Highlights

Colorectal cancer (CRC) is the third most common cancer with respect to global mortality [1].The majority of deaths are due to the development of colorectal liver metastasis (CRLM) as the liver is the most ominous site of distant metastatic spread in CRC patients, often heralding demise [2].Despite advancements in surgical interventions and chemotherapeutics, CRLM morbidity is a leading healthcare concern emphasizing the need to define contributing mechanisms
In previous work of an animal preclinical model contrasted with humans, we found a structural translocation in the distribution of a downstream VEGF-effector, biliary glycoprotein (BGP-CEACAM-1), in livers bearing metastasis in the human [7]
Increased p38γ and pp38γ in CRC Patients Compared to Normal Subjects

Summary

Introduction

The majority of deaths are due to the development of colorectal liver metastasis (CRLM) as the liver is the most ominous site of distant metastatic spread in CRC patients, often heralding demise [2]. Despite advancements in surgical interventions and chemotherapeutics, CRLM morbidity is a leading healthcare concern emphasizing the need to define contributing mechanisms. In previous work of an animal preclinical model contrasted with humans, we found a structural translocation in the distribution of a downstream VEGF-effector, biliary glycoprotein (BGP-CEACAM-1), in livers bearing metastasis in the human [7]. This suggested a paraneoplastic hepatopathy but patients with all-cause cirrhosis and hepatitis did not demonstrate this translocation. As part of the current effort to define contributing mechanisms, our goal was to Vaccines 2020, 8, 720; doi:10.3390/vaccines8040720 www.mdpi.com/journal/vaccines

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