Abstract
Ghrelin system comprises a complex family of peptides, receptors (GHSRs), and modifying enzymes [e.g. ghrelin-O-acyl-transferase (GOAT)] that control multiple pathophysiological processes. Aberrant alternative splicing is an emerging cancer hallmark that generates altered proteins with tumorigenic capacity. Indeed, In1-ghrelin and truncated-GHSR1b splicing variants can promote development/progression of certain endocrine-related cancers. Here, we determined the expression levels of key ghrelin system components in neuroendocrine tumor (NETs) and explored their potential functional role. Twenty-six patients with NETs were prospectively/retrospectively studied [72 samples from primary and metastatic tissues (30 normal/42 tumors)] and clinical data were obtained. The role of In1-ghrelin in aggressiveness was studied in vitro using NET cell lines (BON-1/QGP-1). In1-ghrelin, GOAT and GHSR1a/1b expression levels were elevated in tumoral compared to normal/adjacent tissues. Moreover, In1-ghrelin, GOAT, and GHSR1b expression levels were positively correlated within tumoral, but not within normal/adjacent samples, and were higher in patients with progressive vs. with stable/cured disease. Finally, In1-ghrelin increased aggressiveness (e.g. proliferation/migration) of NET cells. Altogether, our data strongly suggests a potential implication of ghrelin system in the pathogenesis and/or clinical outcome of NETs, and warrant further studies on their possible value for the future development of molecular biomarkers with diagnostic/prognostic/therapeutic value.
Highlights
Neuroendocrine tumors (NETs) comprise a heterogeneous group of relatively rare neoplasias with a primary site originated in the gastrointestinal tract, the pancreas and the lung [1]
Earlier studies suggested that the ghrelin system, which participates in various endocrine-related tumors [9, 10, 21], might play a relevant role in NET pathophysiology
To date, it is still unclear whether the expression profiles of these or other components of the ghrelin system are altered in NETs
Summary
Neuroendocrine tumors (NETs) comprise a heterogeneous group of relatively rare neoplasias with a primary site originated in the gastrointestinal tract, the pancreas and the lung [1]. Gastro-entero-pancreatic NETs (GEP-NETs) are the most common type of tumors, and have been classified by the World Health Organization into three categories (G1, G2 and G3) based on tumor size, histopathological differentiation, proliferation index (Ki-67), hormonal behavior, neuroendocrine biomarkers (such as serotonin and chromogranin A), direct invasion, and distant metastasis [4,5,6]. This classification is useful to predict prognosis and postoperative recurrence, diagnosis of NETs is frequently delayed several years, probably due to the rare and heterogeneous nature of NETs and the nonspecific initial symptoms. Identification of new molecular diagnostic/prognostic markers, to better define their tumor behavior, from proliferation and metastasis to secretory mechanisms, deem necessary to provide clues for novel therapeutic targets [7, 8]
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