br Conclusion br Introduction Gastric
Introduction Gastric adenocarcinoma (GA) is the fifth most commonly diagnosed malignancy and the third most common cause of death due to cancer worldwide. It is a highly aggressive cancer and 5-year survival rate (5YSR) is usually <30% . In fact, the majority of these patients are identified in the late stages based on the endoscopic investigations and most widely used morphological classification introduced by Lauren , that was grouped GA as intestinal (well differentiated and slowly growing) and diffuse (poorly differentiated and aggressive) types. Accordingly, finding more sensitive and specific novel biomarkers for GA is required to assist in earlier diagnosis, classifying patients for personalized medicine and for improving the low survival outcome [3,4]. During cancer progression, tumor cells acquire comprehensive metabolic reprogramming, and tissue hypoxia is a prominent feature of solid tumors leading to cell metabolism adaptive changes. Hypoxia-inducible factor-1α (HIF-1α) is a key oxygen-regulated transcriptional activator, playing a fundamental role in the adaptation of tumor cells to hypoxia by upregulating the transcription of target genes related to multiple biological processes, including cell survival, proliferation, angiogenesis and anti-apoptosis [, , , , ]. In response to hypoxia, most malignant cells often exhibit a metabolic alteration toward anabolic pathways to synthesize their requirements that support the growth of cancer cells. Thus, abnormal fatty ezh2 pathway synthesis might be one of the critical biosynthetic tumor features that interferes with hypoxia and HIF . As a sole mammalian enzyme capable of de novo lipogenesis (DNL), fatty acid synthase (FASN) was observed to be overexpressed in tumor tissues such as pancreas and breast cancers regardless of the extracellular lipid availability [, , ]. On the other hand, sterol regulatory element-binding protein (SREBP) is the central transcription factor to regulate fatty acid synthesis, suggesting that SREBP may have a pivotal role in regulation of lipogenesis by HIF-1α [, , ].
Materials and methods
Discussion GA is among the most common lethal malignancies worldwide [1,3,4]. The revelation of lipid metabolic alterations along GA tumorigenesis pathways could lead to a new approach for earlier detection, efficient prediction and favorable therapeutic strategies. Deregulated growth is the most apparent feature of malignant cells resulting in the increased expenses of oxygen and induction of hypoxia in solid tumors. This induces the stabilization and activation of the HIF-1α, a crucial transcriptional regulator in the adaptation of tumor cells to pathologic hypoxia [6,7]. Our study results not only further depict that HIF-1α gene expression is significantly enhanced in patients with GA, but also found that elevated level of circulating HIF-1α was indeed correlated with GA, considering clinicopathological parameters such as undifferentiated tumor and poor patient survival. This report is consistent with previous data in other cancer types proposing that HIF-1α overexpression occurs early in tumorigenesis . Moreover, it has been shown that in some cancers, HIF-1α upregulation associated directly with loss of differentiation, highly aggressive disease and poor patient outcome [5,19]. Here, we also demonstrated that local gene expression of FASN is increased in patients with GA. In support of this idea, former in vitro studies showed that FASN upregulation could be a substantial factor in cellular growth, transformation and carcinomatous potential, and could thus be considered to act as an oncogene-like contributor [11,13]. A previous research showed that FASN interacts with caveolin-1 on the membrane microdomains of prostate cancer cells . It was observed that proliferative structures like neuronal stem cells require FASN to guarantee their rapid growth [21,22]. Our data suggested that low oxygen availability in GA tumor tissues along with HIF-1α induction might lead to upregulation of FASN. Furthermore, despite being an intracellular protein, we found circulating FASN level in GA cases was significantly higher compared to controls, suggesting that the gastric tumor was the primary source of systematic FASN upregulation in our GA patients. Based on other works, elevated FASN levels have been identified in the sera of pancreas and breast cancers [12,13]; that is in line with our findings. We also observed a significantly high expression of FASN in subjects with diffuse rather than intestinal type of GA. Recent studies indicated that FASN is a prerequisite for rapid cell growth, higher proliferation rates and tumor survival, forming an aberrant and vicious proliferation cycle that is involved in cell phenotype transformation and tumor development [, , ]. Moreover, our data demonstrated that the elevated blood level of FASN in GA patients correlates with higher undifferentiation, shorter time to death and poor prognosis that is in parallel with other works [11,12]. Altogether, we suggested that FASN overexpression is intensely related to the development of GA.