Attribution of Ghrelin to Cancer; Attempts to Unravel an Apparent Controversy

Abstract

Ghrelin is an endogenous peptide hormone mainly produced in the stomach. It has been known to regulate energy homeostasis, stimulate secretion of growth hormone, and mediate many other physiologic effects. Various effects attributed to ghrelin contribute to many aspects of cancer development and progression. Accordingly, a large body of evidence has emerged about the association of ghrelin with several types of cancer in scales of cell-line, animal, and human studies. However, existing data are controversial. This controversy occurs in two main domains: one is the controversial results in local effects of ghrelin on different types of human cancer cell-lines; the second is the apparent disagreement in the results of in-vitro and clinical studies that investigated ghrelin association to one type of cancer. These inconsistencies have hampered the indications to consider ghrelin as a potential tumor biomarker or therapeutic agent in cancer patients. Previous studies have reviewed different parts of current literature about the ghrelin-cancer relationship. Although they have highlighted these controversial results in various ways, no specific recommendations have been given to address it. In this study, we comprehensively reviewed in-vitro, in-vivo, and clinical studies and attempted to use the following approaches to unravel the inconsistencies detected: (a) to distinguish local and systemic effects of ghrelin in interpreting its summary clinical role in each cancer; (b) scrutinizing factors that regulate local effects of ghrelin and could justify different effects of ghrelin on different cancer cell-lines. These approaches could have notable implications for future in-vitro and clinical studies.

Keywords: cancer; carcinogenesis; ghrelin; orexigenic; prognosis.

Figure 1

Overview of biological functions of ghrelin in body. Ghrelin is mainly produced in des-acylated form by gastric oxyntic gland and is acylated to active ghrelin by GOAT enzyme. Ghrelin exerts its biological effects through binding to GHR-1, which is expressed predominantly on hypothalamus and less on other organs. In contrast, des-acylated ghrelin functions as ghrelin antagonist and inhibits the function of ghrelin.

Figure 2

Gene transcription, alternative splicing, and post-translational modifications of ghrelin. Ghrelin is encoded by GHRL gene, which also can produce peptides other than native ghrelin through alternative splicing. Exon 3-deleted peptide lacks the exon number 3 and In1-ghrelin is product of a messenger RNA, which retains the intron-1 transcript of GHRL gene. The initial form of each peptide contains a N-terminal signal peptide that is cleaved by signal peptidase in the endoplasmic reticulum and gives rise to proghrelin, exon 3-deleted proghrelin, and pro-In1-ghrelin. By further post-translational processing, proghrelin is cleaved to produce different peptides.

Figure 3

Model proposed to describe summary clinical role of ghrelin in case of each cancer. The figure summarizes the potential local and systemic effects of ghrelin attributable to cancer biology (items listed in two purple boxes) as wells as the candidate factors that regulate these effects (the items inside surrounding circles). Furthermore, the potential mechanisms proposed so far for local effects of ghrelin are listed in the purple box below the list of local effects. The superscript numbers above each local effect correspond to the potential underlying mechanism(s) from the mechanisms list. The summary clinical role of ghrelin is built-up by relative contributions of local and systemic effects. Based on the direction and relative dominance of local and systemic effects, the summary effect on different aspects of cancer (the items in red box) could be promoting or protective.