CD133 facilitates epithelial-mesenchymal transition through interaction with the ERK pathway in pancreatic cancer metastasis

Ding, Qiang; Miyazaki, Yasuhiro; Tsukasa, Koichiro; Matsubara, Shigeo; Yoshimitsu, Makoto; Takao, Sonshin

doi:10.1186/1476-4598-13-15

Cited by 77 publications

(77 citation statements)

References 25 publications

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“…In a previous study, we revealed that CD133 + LCSCs mediate radiation resistance in human HCC by regulating MAPK signaling pathways (47). In addition, a recent study revealed that CD133 expression was modulated by the ERK1/2 and Src signaling pathways in pancreatic cancer and that CD133 promoted cancer invasion and metastasis by activating an EMT regulatory feedback loop (48). CD44 maintains the high basal level of motility in breast cancer cells by forming a complex with ERK1 and 2, and CD168 (15).…”

Section: Discussionmentioning

confidence: 99%

ELK3 promotes the migration and invasion of liver cancer stem cells by targeting HIF-1α

et al. 2016

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Abstract. Hepatocellular carcinoma (HCC) is the fifth most common solid cancer and the third most common cause of cancer-related mortality. HCC develops via a multistep process associated with genetic aberrations that facilitate HCC invasion and migration and promote metastasis. A growing body of evidence indicates that cancer stem cells (CSCs) are responsible for tumorigenesis, cancer cell invasion and metastasis. Despite the extremely small proportion of cancer cells represented by this subpopulation of HCC cells, CSCs play a key role in cancer metastasis and poor prognosis. ELK3 (Net/SAP-2/Erp) is a transcription factor that is activated by the Ras/extracellular signal-regulated kinase (ERK) signaling pathway. It plays several important roles in various physiological processes, including cell migration, invasion, wound healing, angiogenesis and tumorigenesis. In the present study, we investigated the role of ELK3 in cancer cell invasion and metastasis in CD133 + /CD44 + liver cancer stem cells (LCSCs). We isolated LCSCs expressing CD133 and CD44 from Huh7 HCC cells and evaluated their metastatic potential using invasion and migration assays. We found that CD133 + /CD44 + cells had increased metastatic potential compared with non-CD133 + /CD44 + cells. We also demonstrated that ELK3 expression was upregulated in CD133 + /CD44 + cells and that this aberration enhanced cell migration and invasion. In addition, we identified the molecular mechanism by which ELK3 promotes cancer cell migration and invasion. We found that silencing of ELK3 expression in CD133 + /CD44 + LCSCs attenuated their metastatic potential by modulating the expression of heat shock-induced factor-1α (HIF-1α). Collectively, the results of the present study demonstrated that ELK3 overexpression promoted metastasis in CD133 + /CD44 + cells by regulating HIF-1α expression and that silencing of ELK3 expression attenuated the metastatic potential of CD133 + /CD44 + LCSCs. In conclusion, modulation of ELK3 expression may represent a novel therapeutic strategy for preventing HCC metastasis and invasion.

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Section: Discussionmentioning

confidence: 99%

ELK3 promotes the migration and invasion of liver cancer stem cells by targeting HIF-1α

et al. 2016

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“…CD44 + / CD24 + have a significantly higher possibility for colony formation in vitro (43), and are more resistant to irradiation (43 (23). In addition, CD44, CD24, and EPCAM are now widely used for the identification of pancreatic cancer stem cells (28,(44)(45)(46)(47). In the present study, by using CD44, CD24, and EPCAM, we proved that cantharidin and norcantharidin eliminated the stem-like pancreatic cancer cells, making cantharidin and norcantharidin promising candidates for pancreatic cancer treatment.…”

Section: Discussionmentioning

confidence: 66%

Cantharidin and norcantharidin impair stemness of pancreatic cancer cells by repressing the β-catenin pathway and strengthen the cytotoxicity of gemcitabine and erlotinib

Wang

Shen

et al. 2015

International Journal of Oncology

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Abstract. Increasing evidence suggests that tumors are composed of a heterogeneous cell population with a small subset of cancer stem cells (CSCs) that sustain tumor formation and growth, and are hypothesized to account for therapeutic resistance. Based on the expression of the surface markers CD44, CD24, and EPCAM, putative CSCs have also been identified in pancreatic cancers. It has been well established that aberrant activation of β-catenin signaling pathway may contribute to the maintenance of CSCs. Cantharidin is an active constituent of mylabris, a traditional Chinese medicine. In our previous studies, we demonstrated that cantharidin treatment induced phosphorylation of β-catenin, leading to repression on β-catenin pathway. Therefore, in the present study, we investigated whether cantharidin and its derivant, norcantharidin, could repress the stemness of pancreatic cancer cells through repression on β-catenin pathway. By using microarray and flow cytometry, we found that treatment with cantharidin and norcantharidin repressed the expression of CD44, CD24, and EPCAM at both mRNA and protein levels, leading to decreased CD44 + /CD24 + /EPCAM + proportion, the putative pancreatic CSC subset. Pretreatment with the β-catenin pathway inhibitor FH535, attenuated the cantharidin-and norcantharidin-inducrd repression on CD44, CD24, and EPCAM, suggesting cantharidin and its derivant repressed stemness of pancreatic cancer cells in β-catenin pathway-dependent manner. Furthermore, cantharidin and norcantharidin strengthened the cytotoxicity of gemcitabine and erlotinib, two well established pharmacotherapeutics against pancreatic cancers, indicating cantharidin and norcantharidin could be promising candidates for reversing drug resistance in pancreatic cancers. In conclusion, we presently propose that cantharidin and norcantharidin hold their promise in pancreatic cancer therapy through repression on stemness and strengthening the cytotoxicity of the present therapeutics.

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“…38,39 One recent study indicated that ERK activation by TGF-beta plays a key oncogenic role in Colorectal cancer (CRC) with SMAD4 inactivation mutations. The MEK inhibitor U0126 can surprisingly reduce CT26 cells tumor genesis and liver metastasis in vivo and in vitro, 40 suggesting that MEK inhibitors can be a primary approach for treatment of human malignancies.…”

Section: Discussionmentioning

confidence: 99%

MAPK/ERK Activation Sensitizes MKN-28 Cells to Cisplatin-Induced Apoptosis

Zhang¹,

Liang²,

Zhang³

et al. 2015

Cancer Stud Mol Med Open J

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Cisplatin as a highly potent cytotoxic agent was widely used in the chemotherapy of gastric cancer. It kills cancer cells by inducing apoptosis. The Extracellular signal-regulated kinase (ERK) signaling pathway plays an important role in proliferation and survival. However, its roles in apoptosis vary. This study focused on the role of ERK in cisplatin-induced apoptosis in a stomach cancer cell line, MKN-28 cells. We found that cisplatin treatment substantially activated ERK, which was prevented by MEK inhibitor U0126. Transient transfection of MKN-28 cells with Constitutively Active-MEK1 (CA-MEK1) elevated cisplatin-induced apoptosis comparing with Dominant Negative-MEK1 (DN-MEK1). Cisplatin-induced ERK activation up-regulates pro-apoptotic gene BAK, whereas down-regulates anti-apoptotic gene BCL-2. Knocking down BCL-2 with siRNA sensitizes MKN-28 cells to the toxicity of cisplatin. These results suggested that (1) ERK activation is required for the cisplatin-induced apoptosis in MKN-28 cells; and (2) ERK mediates apoptosis by BCL-2.

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CD133 facilitates epithelial-mesenchymal transition through interaction with the ERK pathway in pancreatic cancer metastasis

Cited by 77 publications

References 25 publications

ELK3 promotes the migration and invasion of liver cancer stem cells by targeting HIF-1α

ELK3 promotes the migration and invasion of liver cancer stem cells by targeting HIF-1α

Cantharidin and norcantharidin impair stemness of pancreatic cancer cells by repressing the β-catenin pathway and strengthen the cytotoxicity of gemcitabine and erlotinib

MAPK/ERK Activation Sensitizes MKN-28 Cells to Cisplatin-Induced Apoptosis

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