Advances in Hypoxia-Mediated Mechanisms in Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the fifth most common and the third most deadly malignant tumor worldwide. Hypoxia and related oxidative stress are heavily involved in the process of HCC development and its therapies. However, direct and accurate measurement of oxygen concentration and evaluation of hypoxic effects in HCC prove difficult. Moreover, the hypoxia-mediated mechanisms in HCC remain elusive. Here, we summarize recent major evidence of hypoxia in HCC lesions shown by measuring partial pressure of oxygen (pO), the clinical importance of hypoxic markers in HCC, and recent advances in hypoxia-related mechanisms and therapies in HCC. For the mechanisms, we focus mainly on the roles of oxygen-sensing proteins (i.e., hypoxia-inducible factor and neuroglobin) and hypoxia-induced signaling proteins (e.g., matrix metalloproteinases, high mobility group box 1, Beclin 1, glucose metabolism enzymes, and vascular endothelial growth factor). With respect to therapies, we discuss mainly YQ23, sorafenib, 2-methoxyestradiol, and celastrol. This review focuses primarily on the results of clinical and animal studies.

The Role of Angiogenesis in Hepatocellular Carcinoma

“…Hypoxia is presumed to robustly stimulate tumor angiogenesis (17,18). Several animal models examining the hypoxic tumor microenvironment in HCC with small fiberoptic sensors or radiographic imaging with oxygen-sensitive probes have shown intratumor oxygen values that were significantly lower than those in normal liver tissue (18)(19)(20). Direct evidence of hypoxia in human HCC is sparse, and results have not been as clear (21).…”

Molecular mechanisms of circular RNAs, transforming growth factor‐β, and long noncoding RNAs in hepatocellular carcinoma

“…Currently, the main treatments for HCC are radiation, chemotherapy, surgical resection, and liver transplantation. 4,5 Some of the key risk factors for HCC include infections by hepatitis C virus (HCV) and hepatitis B virus (HBV). 6 It has | 6685 Shang et al been recognized that the overall survival and life expectancy of HCC patients can be improved through early diagnosis.…”

Hypoxic microenvironment and hepatocellular carcinoma treatment

“…Moreover, recent studies suggest that HMGB1 can also translocate from the nucleus to the cytosol under hypoxia, and then bind to mtDNA released from damaged mitochondria [39] . Subsequent activation of TLR9 signaling pathway promotes HCC proliferation [18,39] , indicating a novel mechanism of the involvement of HMBG1 in HCC progression under hypoxia.…”

“…Yet recently, the findings on the HIFs-independent regulation of tumor angiogenesis and chemoresistance under hypoxic conditions have challenged this notion and raised the possibility that the other important signaling pathways may also participate and promote the progression and malignance of HCC [10][11][12][13][14] . Accumulating evidence shows that Yes associate-Protein (YAP) [17] , matrix metalloproteinases (MMPs), high mobility group box 1 (HMGB1) and glucose metabolism enzymes are involved in hypoxiamediated effects in HCC [18] . The above key molecules would be activated as sensors of intratumoral oxygen tension, and trigger the subsequent activation of hypoxia-mediated process, thus may also be regarded as potential targets for HCC therapy.…”

“…Under hypoxic, HMGB1 activates TLR4 and RAGE signaling pathways to induce caspase-1 activation. Caspase-1 subsequently mediates the cleavage and release of a series of pro-inflammatory cytokines (IL-1β and IL-18), which in turn promote cancer invasion and metastasis [18,40] . Moreover, recent studies suggest that HMGB1 can also translocate from the nucleus to the cytosol under hypoxia, and then bind to mtDNA released from damaged mitochondria [39] .…”