Regulation of Colorectal Carcinoma Stemness, Growth, and Metastasis by an <i>miR-200c</i>-Sox2–Negative Feedback Loop Mechanism

Lu, Yanxia; Li, Yuan; Xue, Xiaolei; Zhou, Min; Liu, Yan; Chao, Zhang; Li, Jingping; Zheng, Lin; Hong, Min; Li, Xuenong

doi:10.1158/1078-0432.ccr-13-2348

Cited by 85 publications

(71 citation statements)

References 47 publications

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“…This resulted in decreased expression of the CSC-associated miR-221 (Fig. 5a), the miR-200 target and stem cell factor SOX2 39 , and by a reduced ability of the cells to form spheres (Fig. 5b).…”

Section: Resultsmentioning

confidence: 99%

CD95 and CD95L promote and protect cancer stem cells

et al. 2014

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CD95 (APO-1/Fas) is a death receptor used by immune cells to kill cancer cells through induction of apoptosis. However, the elimination of CD95 or its ligand, CD95L, from cancer cells results in death induced by CD95R/L elimination (DICE), a type of cell death that resembles a necrotic form of mitotic catastrophe suggesting that CD95 protects cancer cells from cell death. We now report that stimulation of CD95 on cancer cells or reducing miR-200c levels increases the number of cancer stem cells (CSCs), which are more sensitive to induction of DICE than non-CSC, while becoming less sensitive to CD95 mediated apoptosis. In contrast, induction of DICE or overexpression of miR-200c reduces the number of cancer stem cells. We demonstrate that CSCs and non-CSCs have differential sensitivities to CD95-mediated apoptosis and DICE and that killing of cancer cells can be maximized by concomitant induction of both cell death mechanisms.

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Section: Resultsmentioning

confidence: 99%

CD95 and CD95L promote and protect cancer stem cells

et al. 2014

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“…As Aza treatment markedly upregulated the expression levels of miR-200c, the results of the present study suggest that miR-200c may have a suppressive effect on ccRCC cell migration and invasion, and the inhibitory effect of Aza treatment on ccRCC cell migration and invasion may be partly due to the direct upregulation of miR-200c expression levels. A suppressive role of miR-200c in cell migration and invasion has additionally been identified in other types of human cancer (23,24). Liu et al (13) identified that miR-200c inhibited invasion, migration and proliferation of bladder cancer cells.…”

Section: Discussionmentioning

confidence: 98%

“…MicroRNAs (miRs) are a type of small non-coding RNA (19)(20)(21)(22)(23)(24)(25) nucleotides) that possess prominent roles in the regulation of genes (6). MiRs typically inhibit gene expression by directly binding the 3'-untranslated region of their target messenger (m)RNAs, causing repression of translation or mRNA degradation (7).…”

Section: Introductionmentioning

confidence: 99%

Demethylation drug 5-Aza-2′-deoxycytidine-induced upregulation of miR-200c inhibits the migration, invasion and epithelial-mesenchymal transition of clear cell renal cell carcinoma in vitro

Jiang

Sun

et al. 2016

Oncology Letters

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“…In colorectal cancer, miR-200c regulates stemness by targeting Sox2 in a double negative feedback loop, and loss of miR-200c resulted in enhanced expression of stem cell markers (CD166, CD133, and beta-catenin) downstream of Sox2. In the same study, miR-200c-Sox2 feedback loop has also been shown to regulate the PI3K/Akt pathway and control the proliferative and metastatic potential of colorectal cancer via phosphorylation of PI3K by Sox2 [99]. On the contrary, in pancreatic and ovarian cancer, miR-200c has been shown to be directly targeting Zfpm2 and indirectly reducing Pten levels, both of which are negative regulators of the PI3K/Akt pathway [100,101].…”

Section: Mir-200c Regulation Of Signaling Pathwaysmentioning

confidence: 91%

miR-200c: a versatile watchdog in cancer progression, EMT, and drug resistance

et al. 2016

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MicroRNAs (miRNAs) are 20-22-nucleotide small endogenous non-coding RNAs which regulate gene expression at post-transcriptional level. In the last two decades, identification of almost 2600 miRNAs in human and their potential to be modulated opened a new avenue to target almost all hallmarks of cancer. miRNAs have been classified as tumor suppressors or oncogenes depending on the phenotype they induce, the targets they modulate, and the tissue where they function. miR-200c, an illustrious tumor suppressor, is one of the highly studied miRNAs in terms of development, stemness, proliferation, epithelial-mesenchymal transition (EMT), therapy resistance, and metastasis. In this review, we first focus on the regulation of miR-200c expression and its role in regulating EMT in a ZEB1/E-cadherin axis-dependent and ZEB1/E-cadherin axis-independent manner. We then describe the role of miR-200c in therapy resistance in terms of multidrug resistance, chemoresistance, targeted therapy resistance, and radiotherapy resistance in various cancer types. We highlight the importance of miR-200c at the intersection of EMT and chemoresistance. Furthermore, we show how miR-200c coordinates several important signaling cascades such as TGF-β signaling, PI3K/Akt signaling, Notch signaling, VEGF signaling, and NF-κB signaling. Finally, we discuss miR-200c as a potential prognostic/diagnostic biomarker in several diseases, but mainly focusing on cancer and its potential application in future therapeutics.

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Regulation of Colorectal Carcinoma Stemness, Growth, and Metastasis by an miR-200c-Sox2–Negative Feedback Loop Mechanism

Cited by 85 publications

References 47 publications

CD95 and CD95L promote and protect cancer stem cells

CD95 and CD95L promote and protect cancer stem cells

Demethylation drug 5-Aza-2′-deoxycytidine-induced upregulation of miR-200c inhibits the migration, invasion and epithelial-mesenchymal transition of clear cell renal cell carcinoma in vitro

miR-200c: a versatile watchdog in cancer progression, EMT, and drug resistance

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