The Critical Impact of HIF-1a on Gastric Cancer Biology

Abstract

Hypoxia inducible factor-1 (HIF-1) monitors the cellular response to the oxygen levels in solid tumors. Under hypoxia conditions, HIF-1α protein is stabilized and forms a heterodimer with the HIF-1β subunit. The HIF-1 complex activates the transcription of numerous target genes in order to adapt the hypoxic environment in human cancer cells. In gastric cancer patients, HIF-1α activation following extended hypoxia strongly correlates with an aggressive tumor phenotype and a poor prognosis. HIF-1α activation has been also reported to occur via hypoxia-independent mechanisms such as PI3K/AKT/mTOR signaling and ROS production. This article argues for the critical roles of HIF-1α in glucose metabolism, carcinogenesis, angiogenesis, invasion, metastasis, cell survival and chemoresistance, focusing on gastric cancer.

Impaired mitophagy activates mtROS/HIF-1α interplay and increases cancer aggressiveness in gastric cancer cells under hypoxia

“…In GC, previous studies have also reported that HIF-1α activation following extended hypoxia strongly correlates with an aggressive tumor phenotype and poor prognosis of patients (16)(17)(18)(19). Therefore HIF-1α is recognized as a central regulator of GC pathogenesis (14,20). Reactive oxygen species (ROS) such as superoxide are generated mainly through the electron transport chain (ETC) (21,22).…”

“…Under normoxia, prolyl hydroxylases (PHDs) hydroxylate proline residues of HIF-1α in a reaction that uses O 2 as a substrate, and the modified HIF-1α is subsequently degraded by the ubiquitin proteasome system. Under hypoxia, HIF-1α protein is stabilized owing to the absence of O 2 substrate and instead forms a heterodimer with the HIF-1β subunit (11)(12)(13)(14). The HIF-1 complex then activates the transcription of hundreds of target genes and leads to adaptation to the hypoxic environment (11,12 has been reported to upregulate target genes related to energy metabolism, angiogenesis, cell proliferation or survival, invasion or metastasis, and drug resistance in human cancer cells (13)(14)(15).…”

“…Under hypoxia, HIF-1α protein is stabilized owing to the absence of O 2 substrate and instead forms a heterodimer with the HIF-1β subunit (11)(12)(13)(14). The HIF-1 complex then activates the transcription of hundreds of target genes and leads to adaptation to the hypoxic environment (11,12 has been reported to upregulate target genes related to energy metabolism, angiogenesis, cell proliferation or survival, invasion or metastasis, and drug resistance in human cancer cells (13)(14)(15). In GC, previous studies have also reported that HIF-1α activation following extended hypoxia strongly correlates with an aggressive tumor phenotype and poor prognosis of patients (16)(17)(18)(19).…”

Overexpression and correlation of HIF-2α, VEGFA and EphA2 in residual hepatocellular carcinoma following high-intensity focused ultrasound treatment: Implications for tumor recurrence and progression

“…Hypoxia inducible factor-2 subunit α (HIF-2α) is a key factor in angiogenesis, tumor growth and endothelial growth during the remodeling process of tumorigenesis (8 (9). VEGFA is part of the VEGF structural family of proteins, and is among the most potent angiogenic factors expressed in different types of human cancer, including HCC, breast cancer, clear cell renal carcinoma and gastric cancer (10,11).…”

Correlation of P53 Expression with Various Clinicopathological Parameters of Gastric Carcinoma and Its Relationship with Survival

“…Ki67, HIF, E cadherin, MMP-1, TGF-B, STAT3, TIMP1, HER2 in gastric cancer but amongst all, p53 was studied considerably [10][11][12][13][14] . The immunohistochemical protein expression of p53 has been proposed as a potential tool to evaluate the behavior biologically.…”