Hypoxia-Inducible Factor-1 (HIF-1) has been largely studied for its role in cell survival in hypoxic conditions. The regulation of HIF-1 is a complex process and involves a number of molecules and pathways. Among these mechanisms a direct regulatory role of reactive oxygen species (ROS) on HIF-1 alpha subunit has received a great deal of attention and the existing body of literature includes many contradictory findings. Other intermediates such as nitric oxide (NO), specific microRNAs (miR), and transcriptional and post-translational modification have also been implicated as players in ROS mediated HIF-1a regulation. The focus of this review is to present the past conflicting evidence along with more recent findings in order to relate various aspects of this complex process. Aside from the direct role of ROS on HIF-1a regulation under hypoxia and normoxia, we analyzed the effect of different sources and concentrations of NO and the interplay between superoxide (SO) and NO in this process. We also present findings on transcriptional and translational regulation of HIF-1a via ROS and the interplay with microRNAs in this process. This review further provides insight on ERK and PI3K/AKT signaling as a common mechanism relating several pathways of ROS mediated HIF-1a regulation. Ultimately further research and discovery regarding HIF-1 regulation by oxidative stress is warranted for better understanding of disease development and potential therapeutics for pathologies such as cancer, inflammatory diseases, and ischemia-reperfusion injury.

Regulation of Hypoxia‐Inducible Factor‐1a by Reactive Oxygen Species : New Developments in an Old Debate

Mist1 Expressing Gastric Stem Cells Maintain the Normal and Neoplastic Gastric Epithelium and Are Supported by a Perivascular Stem Cell Niche

Gastric cancer (GC) is one of the most common malignancies worldwide with poor prognosis for lack of early detection and effective treatment modalities. The significant influence of tumor microenvironment on malignant cells has been extensively investigated in this targeted-therapy era. Epithelial-mesenchymal transition (EMT) is a highly conserved and fundamental process that is critical for embryogenesis and some other pathophysiological processes, especially tumor genesis and progression. Aberrant gastric EMT activation could endow gastric epithelial cells with increased mesenchymal characteristics and less epithelial features, and promote cancer cell stemness, initiation, invasion, metastasis, and chemo-resistance with cellular adhesion molecules especially E-cadherin concomitantly repressed, which allows tumor cells to disseminate and spread throughout the body. Some pathogens, stress, and hypoxia could induce and aggravate GC via EMT, which is significantly correlated with prognosis. GC EMT is modulated by diverse micro-environmental, membrane, and intracellular cues, and could be triggered by various overexpressed transcription factors, which are downstream of several vital cross-talking signaling pathways including TGF-β, Wnt/β-catenin, Notch, etc. microRNAs also contribute significantly to GC EMT modulation. There are currently some agents which could suppress GC EMT, shedding light on novel anti-malignancy strategies. Investigating potential mechanisms modulating GC cell EMT and discovering novel EMT regulators will further elucidate GC biology, and may provide new biomarkers for early GC detection and potentially efficient targets for preventative and curative anti-GC intervention approaches to prevent local and distant invasions.

Epithelial-mesenchymal transition in gastric cancer.

National Institutes of Health (U.S.) (Grants 54CA126513, R01CA093405, R01CA120979, and R01DK052778)

Wnt5a is involved in activating several non-canonical WNT signaling pathways, through binding to different members of the Frizzled- and Ror-family receptors. Wnt5a signaling is critical for regulating normal developmental processes, including proliferation, differentiation, migration, adhesion and polarity. However, the aberrant activation or inhibition of Wnt5a signaling is emerging as an important event in cancer progression, exerting both oncogenic and tumor suppressive effects. Recent studies show the involvement of Wnt5a in regulating cancer cell invasion, metastasis, metabolism and inflammation. In this article, we review findings regarding the molecular mechanisms and roles of Wnt5a signaling in various cancer types, and highlight Wnt5a in ovarian cancer.

https://www.mdpi.com/2072-6694/8/9/79/pdf

Wnt5a Signaling in Cancer

Background 
Hypoxia-inducible factor 1 (HIF-1α) expression induced by hypoxia plays a critical role in promoting tumor angiogenesis and metastasis. However, the molecular mechanisms underlying the induction of HIF-1α in tumor cells remain unknown.


Methodology/Principal Findings 
In this study, we reported that hypoxia could induce HIF-1α and VEGF expression accompanied by Rac1 activation in MCF-7 breast cancer cells. Blockade of Rac1 activation with ectopic expression of an inactive mutant form of Rac1 (T17N) or Rac1 siRNA downregulated hypoxia-induced HIF-1α and VEGF expression. Furthermore, Hypoxia increased PI3K and ERK signaling activity. Both PI3K inhibitor LY294002 and ERK inhibitor U0126 suppressed hypoxia-induced Rac1 activation as well as HIF-1α expression. Moreover, hypoxia treatment resulted in a remarkable production of reactive oxygen species (ROS). N-acetyl-L-cysteine, a scavenger of ROS, inhibited hypoxia-induced ROS generation, PI3K, ERK and Rac1 activation as well as HIF-1α expression.


Conclusions/Significance 
Taken together, our study demonstrated that hypoxia-induced HIF-1α expression involves a cascade of signaling events including ROS generation, activation of PI3K and ERK signaling, and subsequent activation of Rac1.

/pdf/pi3k-and-erk-induced-rac1-activation-mediates-hypoxia-4vbwpuzew4.pdf

PI3K and ERK-induced Rac1 activation mediates hypoxia-induced HIF-1α expression in MCF-7 breast cancer cells.

PI3K/Akt-dependent phosphorylation of GSK3β and activation of RhoA regulate Wnt5a-induced gastric cancer cell migration.

Rab35 is required for Wnt5a/Dvl2-induced Rac1 activation and cell migration in MCF-7 breast cancer cells.

Wnt5a, a ligand for activating the non-canonical Wnt signaling pathway, is commonly associated with Epithelial-to-mesenchymal transition (EMT) in cancer cell metastasis. Here, we show that downregulation of Wnt5a mRNA and protein by EGF is necessary for EGF-induced EMT in gastric cancer SGC-7901 cells. To further explore the mechanisms, we investigated the effect of EGF signaling on Wnt5a expression. EGF increased Arf6 and ERK activity, while blockade of Arf6 activation repressed ERK activity, up-regulated Wnt5a expression and repressed EMT in response to EGF. We also demonstrate that EGF inactivated Wnt5a transcription by direct recruitment of ERK to the Wnt5a promoter. On the other hand, inhibition of ERK phosphorylation resulted in decreased movement of ERK from the cytoplasm to the nucleus, following rescued Wnt5a mRNA and protein expression and favored an epithelial phenotype of SGC-7901 cells. In addition, we notice that kinase-dead, nuclear-localised ERK has inhibitory effect on Wnt5a transcription. Analysis of gastric cancer specimens revealed an inverse correlation between P-ERK and Wnt5a protein levels and an association between Wnt5a expression and better prognosis. These findings indicate that Wnt5a is a potential suppressor of EMT and identify a novel Arf6/ERK signaling pathway for EGF-regulated Wnt5a expression at transcriptional level of gastric cancer cells.

/pdf/egf-reduced-wnt5a-transcription-induces-epithelial-2jmvtxumr1.pdf

EGF-reduced Wnt5a transcription induces epithelial-mesenchymal transition via Arf6-ERK signaling in gastric cancer cells

Melatonin, a naturally-occurring hormone, possesses antioxidant properties and ameliorates vascular endothelial dysfunction. In this study, we evaluate the impact of melatonin on the migratory capability of human umbilical vein endothelial cells (HUVECs) to hypoxia and further investigate whether ERK/Rac1 signaling is involved in this process. Here, we found that melatonin inhibited hypoxia-stimulated hypoxia-inducible factor-1α (HIF-1α) expression and cell migration in a dose-dependent manner. Mechanistically, melatonin inhibited Rac1 activation and suppressed the co-localized Rac1 and F-actin on the membrane of HUVECs under hypoxic condition. In addition, the blockade of Rac1 activation with ectopic expression of an inactive mutant form of Rac1-T17N suppressed HIF-1α expression and cell migration in response to hypoxia, as well, but constitutive activation of Rac1 mutant Rac1-V12 restored HIF-1α expression, preventing the inhibition of melatonin on cell migration. Furthermore, the anti-Rac1 effect of melatonin in HUVECs appeared to be associated with its inhibition of ERK phosphorylation, but not that of the PI3k/Akt signaling pathway. Taken together, our work indicates that melatonin exerts an anti-migratory effect on hypoxic HUVECs by blocking ERK/Rac1 activation and subsequent HIF-1α upregulation.

Rui Xu

Papers

PI3K and ERK-induced Rac1 activation mediates hypoxia-induced HIF-1α expression in MCF-7 breast cancer cells.

PI3K/Akt-dependent phosphorylation of GSK3β and activation of RhoA regulate Wnt5a-induced gastric cancer cell migration.

Rab35 is required for Wnt5a/Dvl2-induced Rac1 activation and cell migration in MCF-7 breast cancer cells.

EGF-reduced Wnt5a transcription induces epithelial-mesenchymal transition via Arf6-ERK signaling in gastric cancer cells

Melatonin suppresses hypoxia-induced migration of HUVECs via inhibition of ERK/Rac1 activation.