HIF‑1α regulates A2B adenosine receptor expression in liver cancer cells

Abstract

Liver cancer exhibits the fourth most common cause of cancer-associated mortality worldwide. Due to the rapid growth, solid tumors undergo severe hypoxia and produce high levels of extracellular adenosine to maintain homeostasis. A previous study indicated that the hypoxic condition in liver cancer increased hepatic adenosine, which is known to facilitate cancer survival and proliferation. Extracellular adenosine has been revealed to regulate pathological and physiological processes in cells and tissues. However, its pathophysiological role in liver cancer remains undetermined. Emerging evidence has indicated that the adenosine A2B receptor promotes the progression of liver cancer. Therefore, it was hypothesized that HIF-1α is a transcriptional regulator of A2B in human liver cancer. The current study determined A2B expression of a number of liver cancer cell lines and performed functional studies of HIF-1α as a master transcriptional regulator of hepatic A2B signaling during hypoxic conditions. The current study aimed to identify the promoter region of A2B, which has a hypoxia response element, by performing luciferase assays. The present study demonstrated that reduced HIF-1α expression is associated with low expression of A2B, and HIF-1α overexpression is associated with A2B induction. Furthermore, the siRNA-mediated downregulation of A2B inhibited the growth and proliferation of HepG2, which is a liver cancer cell line. The relationship between HIF-1α and A2B expression was also identified in human liver cancer specimens. In conclusion, the current study indicated that A2B is induced by the HIF-1α transcriptional regulator during hypoxia, and it may be a potential pharmacologic and therapeutic target for the treatment of patients with liver cancer.

A control theoretic three timescale model for analyzing energy management in mammalian cancer cells

“…In accordance with previous investigations including some in vivo and in vitro experiments [24] , [27] , [26] , [28] , [29] , [30] , [31] , [32] , [33] , [34] , [35] , [36] , [37] , [38] , [39] , [40] , [41] , [42] , [43] , [44] , [45] , [25] , [46] , [47] , [48] , [49] , [50] , [51] , [52] , [53] , [54] , [55] , [56] , [57] , [58] , [59] , [60] , [61] , [62] , [63] , [64] , [65] , the simulation results also suggest that abnormal over expressions of certain proteins and genes depicted in Table 3 play significant roles to maintain growth, proliferation and energy supply in mammalian cancer cells to survive. Under expressions of prolyl-hydroxylases (PHD) and tumor suppressing protein p53 are also important in this context.…”

“…PHD inhibition promotes more stabilization of HIF-1 in cancer cells than in normal ones [29] , [30] . In this context, Kwon et al [54] has found higher expression level of HIF-1 measured in human hepatocellular carcinoma (HCC) specimens compared to the non-cancerous tissue specimens ( Fig. 10 A).…”

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Fig. 10 It depicts: (A) Higher expression level of HIF-1 measured in human hepatocellular carcinoma (HCC) specimens compared to the non-cancerous tissue specimens [54] , (B) Similar behavior of HIF-1 expression shown by our simulation results, (C) Lower concentration of NADH in cancer cells compared to normar ones as per the in vivo / in vitro experiment performed by Sumi et al [103] , (D) Similar behavior of NADH depicted by our computational results.

Fig.

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“…In support of our simulation results, we have found some previous investigations, including in vivo and in vitro experiments [28] , [29] , [30] , [31] , [32] , [33] , [34] , [35] , [36] , [37] , [38] , [39] , [40] , [41] , [42] , [43] , [44] , [64] , [65] , which show similar kinds of behavior. Besides, we have collected the recent in vivo / in vitro data [54] , [56] , [57] , [55] , [58] , [59] , [60] , [61] , [62] , [63] of human cancer cells to compare different mutations verified in experimental laboratories with our simulation results. Here, we have normalized the experimental data in .…”

Bone Marrow and Adipose Tissue Adenosine Receptors Effect on Osteogenesis and Adipogenesis

“…Similarly, the A2bAR is upregulated by inflammation, hypoxia and extracellular adenosine [ 22 , 23 , 24 , 25 ]. Expression of the A2bAR is upregulated in conditions of inflammation or hypoxia in the vasculature, intestine, kidneys, heart and lung [ 9 , 19 , 26 , 27 ]. Not only does the variable and inducible expression of adenosine receptors indicate the complexity of adenosine receptor signaling, it also indicates the consideration that must be taken when designing therapeutics.…”