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  • In the present study fasting blood glucose and insulin level


    In the present study, fasting blood glucose and insulin levels were not significantly different between GA patients and control cases. Normal mammalian cells typically acquire fatty acids from the circulation owing to insulin, which is the most lipogenic hormone in the subset of adult tissues, including liver, adipose and lactating mammary gland [11,24]. In contrast, it was suggested that some cancer types depend on de novo fatty KY 02111 sale biosynthesis that could be regulated by the transcription factor SREBP-1c [26]. As a result, unrestricted fatty acid anabolism could be observed in cancers [11,14,15], unaffected by the extracellular lipid availability and regulatory hormonal motivation [24]. Previous studies found that SREBP acts as an oxygen sensor in fission yeast [27] and to be required for the conservation of cell size in Drosophila. Melanogaster [28]. SREBP-1c is a transcription factor of the basic helix-loop-helix leucine zipper (bHLHLZ) that indeed leads to lipid homeostasis in mammals. It has a regulatory role during mitosis, showing that the expression of lipogenic genes is a prerequisite for cell-cycle progression. To address the pathway underlying HIF-1α-induced FASN upregulation, we tested SREBP-1c expression in GA. Based on our current findings, SREBP-1c gene upregulated in GA tumor tissues compared to controls. Elevated mRNA expression of SREBP-1c was also supported by our IHC data, which revealed SREBP-1c overexpression in the majority of tumor sections. Moreover, the SREBP-1c expression was associated significantly with patient shorter survival. In keeping with our findings, SREBP-1c has been shown to be present in atypically hyperplastic tissues including glioblastoma multiforme and pancreatic cancers [14,15]. In vitro studies demonstrate that SREBP-1c encourages cell growth and metastasis [[28], [29], [30]]. In the present study, we also showed that the HIF-1α overexpression was accompanied with the highly expressed genes of FASN and SREBP-1c, indicating that SREBP-1c and FASN genes could be subject to the same regulatory mechanisms in the human GA progression. In addition, our in vitro studies provide evidence that hypoxia induced-HIF-1α could be responsible for the stimulation of FASN, and SREBP-1c may have a direct role in hypoxia-induced FASN expression in human gastric adenocarcinoma AGS cell line. To confirm our findings, it was observed that SREBP-1c could be as a target gene of HIF-1α [15,16]. Furthermore, silencing of SREBP-1c expression dramatically decreases lipogenesis and inducing apoptosis in some cancers types [31,32]. Consequently, HIF-1α induction accompanied with FASN and SREBP-1c upregulation seems to be a survival approach of GA cells in hypoxic condition, by metabolic alteration toward lipogenic pathway.
    Conflicts of interest
    Ethical statement and informed consent
    Introduction Angiogenesis is triggered by several stimuli during tumor growth such as HIF-1α. VEGF is a downstream target of HIF-1α, which is a transcription factor responsible for the regulation of cell response to hypoxia (Semenza, 2001). HIF-1α also controls oxygen homeostasis (Semenza, 2001). Hypoxia is common in the tumor microenvironment because of physical and functional changes in blood vessels as well as increased consumption of oxygen due to rapid tumor cell growth (Harris, 2002). The principal factors in determining angiogenesis are HIF-1α and hypoxia. These factors also control invasion and metastasis, which ultimately determines aggressiveness of tumor cells (Koh et al., 2011). Expression of VEGF in hypoxic cells is induced by HIF-1α via binding to the VEGF promoter (Semenza, 2001). Investigations have revealed that increased expression of HIF-1α is connected with therapeutic resistance and poor prognosis (Vaupel et al., 2001). Many phytochemicals, including isoflovanoids, are capable of inhibiting HIF-1α (González-Vallinas et al., 2013; Dandawate et al., 2016). Isoflavones can block BC progression by inhibiting enzymes that are vital for signal transduction, metastasis, as well as, DNA replication by blocking growth factors (VEGF) and lastly by stimulating the immune system (Valachovicova et al., 2004; Khan et al., 2011). A natural isoflavone, genistein acts as an estrogen derivative (Nagaraju et al., 2013). Genistein has been found to inhibit several cancer types such as colorectal, pancreatic and breast cancers by interfering with pathways that regulate apoptosis and survival, thereby targeting essential molecules (Nagaraju et al., 2013). Most of the patients with BC suffer from an ER–positive tumor (Prat et al., 2013). Genistein induces apoptosis in BC cells with differential ER grade (Yang et al., 2007), indicating that it can be used as a new therapeutic agent for BC treatment. Although the exact mechanisms of action of genistein remain unknown, a study in lung cancer indicated that genistein can reduce cell viability by inhibiting the PI3K/AKT and HIF-1α pathways (Zhang et al., 2017). Another study also demonstrated that genistein can counter HIF-1α upregulation (Zhou and Liu, 2013). The main aim of this investigation was thus to examine the genistein-HIF-1α interaction and to identify the consequence of HIF-1α inhibition on BC cells. Docking analysis was also executed to define the residues involved in genistein's downregulatory action on HIF-1α.