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.
Highlights
Ghrelin is a peptide hormone that was discovered as an intrinsic ligand for growth hormone secretagogue receptor (GHSR) [1]
GHSR1a and GHSR1b expressions were significantly correlated with In1-ghrelin level, while none of these receptors correlated with native ghrelin expression [12]
Des-acylated ghrelin and Tamoxifen upregulated ghrelin expression in the malignant cell line, they reduced In1-ghrelin expression. Because these effects were not seen by estradiol, authors postulated that Tamoxifen affects ghrelin expression by an estrogen receptor (ER)-independent manner [12]
Summary
Ghrelin is a peptide hormone that was discovered as an intrinsic ligand for growth hormone secretagogue receptor (GHSR) [1]. In-vitro studies reported stimulatory effects of ghrelin on proliferation and invasion of gastric cancer cell lines [37, 47], the clinical studies linked ghrelin to a reduced incidence [48, 49], and better prognosis [50]. Expression of Native Ghrelin Peptide Among 144 patients with invasive breast cancer, 88.2% had ghrelin positive tumor cells (Table 1; Supplementary Table 1). Fulllength and exon 3-deleted pre-proghrelin was transcribed both in benign, MCF-10A, and malignant breast cancer cell lines, MDA-MB-231, MCF-7, MDA-MB-435, and T47D. Exon 3-deleted preproghrelin showed more intense expression in cancerous compared to normal breast tissues. Expression of In1-ghrelin was 8-fold upregulated in high-grade breast tumor samples relative to normal tissues Expression of this variant was highly correlated with proliferation and mitotic markers, Ki-67 and cyclin D3. Because these effects were not seen by estradiol, authors postulated that Tamoxifen affects ghrelin expression by an ER-independent manner [12]
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