Stem cell factor/c-kit signaling enhances invasion of pancreatic cancer cells via HIF-1α under normoxic condition☆

Zhang, Min; Ma, Qingyong; Hu, Hengtong; Zhang, Dong; Li, Junhui; Ma, Guodong; Bhat, Kruttika; Wu, Erxi

doi:10.1016/j.canlet.2011.01.017

Cited by 41 publications

(35 citation statements)

References 45 publications

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“…The expression and activity of HIF-1α are regulated in tumor development by multiple signaling pathways and proteins, including PKC/P13K/AKT/mTOR (35)(36)(37), Ras/MEK/ERK (38), MAPK (39,40), EGFR and IGF1R autocrine signaling (41), PTEN (37,42,43). Under hypoxic condition, stabilized HIF-1α protein dimerizes with HIF-1β in the nucleus and the complex binds to a core DNA hypoxia response element (HRE) (44), activating the expression of numerous tumor promoter genes, including GLUT1 (10), VEGF (45), NOS (46), IGF-2 (47) and ID2 (48).…”

Section: Discussionmentioning

confidence: 99%

KLF5 promotes hypoxia-induced survival and inhibits apoptosis in non-small cell lung cancer cells via HIF-1α

Liu

et al. 2014

International Journal of Oncology

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Abstract. Transcription factor Krüppel-like factors 5 (KLF5) is overexpressed in a wide range of tumor tissues and acts as a prognostic factor in cancer. However, the role of KLF5 in non-small cell lung cancer is not clear. Hypoxia plays a vital part in the development of cancer via hypoxia-inducible factor 1 (HIF-1). Our study showed that hypoxia (1% O 2 ) increased cell viability, clonality and proliferation and inhibited cell apoptosis in A549 cells. The expression of HIF-1α and KLF5 was increased time-dependently in hypoxia. Using small interfering RNA (siRNA) targeting KLF5 or HIF-1α, we demonstrated that KLF5 or HIF-1α knockdown inhibited hypoxia-induced cell survival and promoted cell apoptosis by actively downregulating cyclin B1, survivin and upregulating caspase-3. Given the similar effect of KLF5 and HIF-1α on cell survival, an attempt was made to investigate the putative interaction of them in hypoxia. KLF5 was revealed to co-immunoprecipitate with HIF-1α and hypoxia increased the amount of KLF5 and HIF-1α complex. Moreover, silencing of KLF5 decreased HIF-1α expression while KLF5 was not affected by HIF-1α inhibition in hypoxia, confirming the effect of KLF5 on upregulation of HIF-1α. In conclusion, this study identified hypoxia as a tumor promoter by triggering KLF5 → HIF-1α → cyclin B1/survivin/caspase-3 in lung cancer cells.

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Section: Discussionmentioning

confidence: 99%

KLF5 promotes hypoxia-induced survival and inhibits apoptosis in non-small cell lung cancer cells via HIF-1α

Liu

et al. 2014

International Journal of Oncology

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“…Cisplatin treatment is known to induce a variety of survival signalings, including hypoxia-inducible factor (HIF)-1 or Akt signalings [8,18,20]. HIF-1 induction is reported to induce SCF; SCF can up-regulate HIF-1 transcription, thereby forming a positive activation loop, which must promote angiogenesis in vivo [5,14,26]. Such a microenvironment will disturb the effect of cisplatin or induce resistance in vivo.…”

Section: Discussionmentioning

confidence: 99%

Imatinib sensitizes endometrial cancer cells to cisplatin by targeting CD117-positive growth-competent cells

et al. 2014

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a b s t r a c tThe use of molecular target therapy has not been established for endometrial cancer. The present study investigated the potential therapeutic strategy of targeting CD117-positive cancer cells as a novel molecular target therapy. FACS-sorted CD117 + cells isolated from endometrial cancer cell lines (Ishikawa or MFE280 cells) exhibited higher proliferative capacity in vitro and colony forming activity on soft agar, and decreased sensitivity to cisplatin, compared to CD117 À cells. Immunohistochemical analyses with surgical specimens of endometrial cancers showed that high CD117 expression was tightly linked to advanced FIGO stages, myometrial invasion and histological grade, and was significantly associated with poor overall survival and relapse-free survival (Kaplan-Meier analysis; p < 0.001, log-rank test). The Cox-regression hazard model identified high CD117 expression to be an independent prognostic factor for survival (p < 0.05). In vitro assay confirmed that stem cell factor (SCF), a ligand of CD117, was produced specifically in CD117 + cells of endometrial cancer, and the colony-forming activity were abrogated by adding anti-SCF antibody, indicating an SCF-dependent growth property. Imatinib was confirmed to selectively target CD117 + cells in vitro, and synergistically enhanced the anti-tumor effect of low dose cisplatin in vivo, which showed only modest effects when used as a single use. These findings suggest that CD117 can be a marker of aggressive behavior of cells as well as an independent prognostic marker in endometrial cancer. Targeting of the SCF/CD117 axis by imatinib sensitized endometrial cancer cells to cisplatin, proposing a novel therapeutic strategy for this tumor type.

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“…Pancreatic cancer is a highly malignant tumor of the gastrointestinal cancer with a 5-year survival rate of less than 5% [8][9][10][11][12]. As a result of hypoxia and genetic mutations, hypoxia inducible factor-1 (HIF-1) is highly expressed in pancreatic cancer cells [13,14], which is predominant in regulating hypoxia-related genes in pancreatic cancer.…”

Section: Introductionmentioning

confidence: 99%

Hypoxia inducible factor (HIF)-1α directly activates leptin receptor (Ob-R) in pancreatic cancer cells

et al. 2014

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Stem cell factor/c-kit signaling enhances invasion of pancreatic cancer cells via HIF-1α under normoxic condition☆

Cited by 41 publications

References 45 publications

KLF5 promotes hypoxia-induced survival and inhibits apoptosis in non-small cell lung cancer cells via HIF-1α

KLF5 promotes hypoxia-induced survival and inhibits apoptosis in non-small cell lung cancer cells via HIF-1α

Imatinib sensitizes endometrial cancer cells to cisplatin by targeting CD117-positive growth-competent cells

Hypoxia inducible factor (HIF)-1α directly activates leptin receptor (Ob-R) in pancreatic cancer cells

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