HIF-1α and HIF-2α correlate with migration and invasion in gastric cancer

Wang, Yanxia; Li, Zhichao; Zhang, Hongbo; Jin, Haifeng; Lee, Sun; Dong, Huijuan; Xu, Meifeng; Zhao, Peng; Zhang, Bo; Wang, Jin; Pan, Yanglin; Liu, Huan

doi:10.4161/cbt.10.4.12441

Cited by 55 publications

(49 citation statements)

References 34 publications

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“…Although hypoxia is cytotoxic to both normal and cancer cells, some cancer cells acquire characteristics that allow them to survive and grow under hypoxic conditions (such as, expression of angiogenic factors, glycolytic enzymes and stress proteins). In addition, these ischemic conditions contribute to the aggressive metastatic phenotypes of tumor cells, and metastasis, which is characterized by migration, seeding and growth of satellite lesions in specific organs, is commonly considered to be the final stage of cancer (11,(31)(32)(33)(34). Experimental and clinical data provided evidence for a relationship between intratumoral hypoxia and aggressive behavior in solid tumors, including gastric cancer (35)(36)(37)(38)(39).…”

Section: Discussionmentioning

confidence: 99%

“…Intratumoral hypoxia is a common feature of solid tumors and an important microenvironmental factor that drives aggressive behavior in cancer (9,11). After being exposed to hypoxia, several types of cancer cells increase their synthesis of a protein called hypoxia-inducible factor (HIF), which in turn binds to and transactivates target genes (12).…”

Section: Introductionmentioning

confidence: 99%

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Hypoxia induces CXCR4 expression and biological activity in gastric cancer cells through activation of hypoxia-inducible factor-1α

Kim

Song

et al. 2012

Oncology Reports

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Abstract. Given the important role of CXCR4 in cancer metastasis, microenvironmental factors that modulate CXCR4 may have an impact on the process of tumor expansion. Hypoxia is a common feature of solid tumors and a significant microenvironmental factor that drives aggressive behavior. CXCR4 is upregulated in several cancer cells under hypoxic conditions, suggesting a relationship between tumor hypoxia and CXCR4. However, the role of hypoxia in regulating CXCR4 in gastric cancer remains poorly understood. KATO III gastric cancer cells were exposed to hypoxia or normoxia. CXCR4 expression in cells transfected with shRNA specific for HIF-1α was investigated by western blotting and flow cytometry. Wound healing, migration and invasion assays were used to assess cell motility and the chemotactic response to CXCL12, a major CXCR4 ligand. CXCR4 expression at the protein level and in the cell membrane was significantly increased in KATO III cells following exposure to hypoxia. This upregulation of CXCR4 was implicated in increased cell motility and enhanced chemotactic responses (migration and invasion) to CXCL12 treatment in vitro. The increases in CXCR4 expression and metastatic potential in gastric cancer cells exposed to hypoxia were blocked by HIF-1α-specific shRNA. Our results indicate that hypoxia upregulates CXCR4 in gastric cancer cells in a HIF-1α-dependent manner, and that upregulation of CXCR4 plays a role in cancer cell migration and invasion. Thus, disrupting the hypoxia-HIF-1α-CXCR4 axis could be an attractive therapeutic strategy for the treatment of gastric cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hypoxia induces CXCR4 expression and biological activity in gastric cancer cells through activation of hypoxia-inducible factor-1α

Kim

Song

et al. 2012

Oncology Reports

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“…HIF is a heterodimer consisting of an oxygen-dependent α subunit and a constitutively expressed β subunit (9). Previous studies have demonstrated that HIF-1α is overexpressed in gastric cancer (13)(14)(15); furthermore, HIF-1α is associated with metastatic potential in gastric cancer cells via undefined underlying mechanisms (10).…”

Section: Introductionmentioning

confidence: 99%

“…Hypoxic tumor microenvironments induce phenotypic changes that make cancer cells aggressive (9,10), refractory to treatment (11) and likely to metastasize (12). These phenotypic changes are mediated by hypoxia-inducible factors (HIFs) (12).…”

Section: Introductionmentioning

confidence: 99%

Hypoxia regulates CD44 expression via hypoxia-inducible factor-1α in human gastric cancer cells

Liang

et al. 2016

Oncology Letters

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Abstract. Hypoxia induces proliferation and invasion in cancer cells via hypoxia-inducible factor (HIF)-1α. The cell adhesion molecule cluster of differentiation (CD) 44 has been associated with increased cell invasion and metastasis. Whether hypoxia regulates the expression of CD44 in gastric cancer cells remains to be established. In the current study, the effects of hypoxia on HIF-1α and CD44 expression levels in human gastric cell lines SGC-7901 and BGC-823 were evaluated. The cells were cultured in 1% O 2 for 1 week and then treated with 20 nM rapamycin for 72 h. Cell viability was evaluated using the Cell Counting kit-8 assay, and cell invasion was detected by the Transwell invasion assay. The protein and messenger (m) RNA expression levels of HIF-1α and CD44 were detected using western blotting and reverse transcription-quantitative polymerase chain reaction, respectively. The results revealed that cell viability and invasion increased under hypoxic conditions, but decreased following rapamycin treatment in SGC-7901 and BGC-823 cells. Hypoxia also increased the protein and mRNA expression levels of HIF-1α and CD44 in these two cell lines. However, this hypoxia-induced increase in HIF-1α and CD44 protein and mRNA expression levels was inhibited by rapamycin. These findings suggest that hypoxia induced the proliferation and invasion of SGC-7901 and BGC-823 cells. Furthermore, CD44 expression levels were potentially associated with HIF-1α expression levels. Therefore, in gastric cancer cells, hypoxia may regulate CD44 expression via HIF-1α in order to promote cell proliferation and invasion.

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“…HIF-1 upregulation is an early event of cells in hypoxia that triggers hypoxia-related gene transcription (6). HIF-1 can promote tumor angiogenesis, drug resistance and cell migration by binding with downstream HRE (7,8).…”

Section: Introductionmentioning

confidence: 99%

Krüppel-like factor 8 involved in hypoxia promotes the invasion and metastasis of gastric cancer via epithelial to mesenchymal transition

Liu¹,

Wang²,

Zhou³

et al. 2014

Oncology Reports

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Abstract. Previously, we reported that hypoxia was able to induce invasion and metastasis in gastric cancer and that hypoxia-inducible factor-1 (HIF-1) is a key factor involved in this tumor type. Krüppel-like factor 8 (KLF8) as a transcriptional repressor has been suggested as a promoter of tumor metastasis in breast cancer and an inducer of the epithelial-mesenchymal transition (EMT). KLF8 is also highly expressed in gastric cancer tissues, contributing to poor prognosis. However, the association between KLF8 and HIF-1 in regulating the progression of human gastric cancer in hypoxia is unclear. In the present study, we found that KLF8 was overexpressed in gastric cancer metastatic tissues and cells. Additionally, KLF8 siRNA significantly inhibited SGC7901 cell invasion and migration compared with SGC7901, SGC7901/Scr-si cells. Hypoxia is thus able to induce KLF8 expression and EMT in SGC7901 cells. However, following the examination of changes in cell morphology and epithelial and mesenchymal markers, it was found that KLF8 siRNA and HIF-1 siRNA strongly reversed EMT in cells undergoing hypoxia. Furthermore, hypoxia-induced KLF8 overexpression was attenuated by HIF-1 siRNA. Experiments using luciferase promoter constructs resulted in a marked increase in the activity of cells exposed to hypoxia and decreased activity in cells co-transfected with HIF-1 siRNA. The chromatin immunoprecipitation assay revealed proximal HRE at -133 is the main HIF-1 binding site in the KLF8 promoter.In conclusion, the results demonstrated that KLF8 is actively enhanced by hypoxia and is a novel HIF-1 target. KLF8 is a novel EMT regulating transcription factor that involved in the progression of gastric cancer. The specific anti-EMT drugs in combination with anti-hypoxia are new promising cancer therapies.

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HIF-1α and HIF-2α correlate with migration and invasion in gastric cancer

Cited by 55 publications

References 34 publications

Hypoxia induces CXCR4 expression and biological activity in gastric cancer cells through activation of hypoxia-inducible factor-1α

Hypoxia induces CXCR4 expression and biological activity in gastric cancer cells through activation of hypoxia-inducible factor-1α

Hypoxia regulates CD44 expression via hypoxia-inducible factor-1α in human gastric cancer cells

Krüppel-like factor 8 involved in hypoxia promotes the invasion and metastasis of gastric cancer via epithelial to mesenchymal transition

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