Expression of Klotho and LRP-6 Proteins in Gastric Adenocarcinoma, is it an Important Issue??

Gastric cancer is the fifth most common malignancy in the world after cancers of the lung, breast, colorectum, and prostate. Gastric cancer is the third leading cause of cancer death and is responsible for 723,000 deaths yearly [1]. Gastric carcinoma (GC) is a multifactorial disease, where many factors can influence its development, both genetic and environmental such as infection with Helicobacter pylori (which is the main risk factor), gastric ulcer disease, gastroesophageal reflux disease and obesity [2]. Furthermore, genetic variations in proinflammatory and anti-inflammatory cytokine genes also influence the individual response to carcinogenic exposures. Host genetic factors are emerging as key determinants of disease risk for many cancers [1].

Gastric carcinoma is difficult to diagnose in early-stage because of a time lag between the onset of growth and the appearance of clinical presentation. Early symptoms of gastric cancer are not specific; as a result, most patients with early gastric cancer present with symptoms indistinguishable from benign peptic ulcer disease and, subsequently, these patients have been diagnosed at an advanced stage GC [1]. So, its prognosis is poor as evidenced by the 5-year survival rate and because most cases are already metastatic when diagnosed [2]. GC mostly affects older people. The average age of people when they are diagnosed with gastric cancer is 68 years [1].

Klotho is anti-aging gene encoding a protein with multiple pleiotropic effects, discovered in 1997 by Kuro-o and colleagues. The Klotho family of proteins consists of three members: α-Klotho, β-Klotho and γ-Klotho. All three are single-pass transmembrane proteins. The α-Klotho gene is composed of five exons, in humans, mice and rats expressed predominantly in the distal convoluted tubule (DCT) cells of the kidney in addition to a lesser expression in the proximal convoluted tubule (PCT) cells [3].

Cancer and ageing share comparable principles; the time-dependent accumulation of DNA damage is a contributing factor in ageing and also drives cancer progression. DNA damage, alongside genomic instability, is an established hallmark of most cancers. These pathways influence a number of capabilities acquired by cancer cells including the ability to evade apoptosis, cause tumor invasion and metastasis, sustain angiogenesis, and facilitate unlimited cellular replicative potential. Alpha-Klotho potentially influences these phenotypes through the inhibition of a number of signaling pathways such as insulin-like growth factor 1 receptor (IGF-1R), fibroblast growth factor (FGF), transforming growth factor β (TGFβ) and wingless-related integration site (Wnt) [4].

Klotho gene has been described as a tumor suppressor gene in numerous solid tumors and hematological malignancies, Klotho represents a possible therapeutic target for patients with these diseases, the majority of whom have limited treatment options [5].