MicroRNA 376c enhances ovarian cancer cell survival by targeting activin receptor-like kinase 7: implications for chemoresistance

Ye, Gang; Fu, Guodong; Cui, Shiying; Zhao, Su-Fen; Bernaudo, Stefanie; Bai, Yin; Ding, Yanfang; Zhang, Yaou; Yang, Burton B.; Peng, Chun

doi:10.1242/jcs.072223

Cited by 113 publications

(86 citation statements)

References 50 publications

(51 reference statements)

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“…Current data suggest that miRNAs could render cancer cells susceptible or resistant to chemotherapy based on their functions and targets. 4,5 In ovarian cancer cells, examples include ectopic expression of miR-214-and miR-376c-enhanced cisplatin resistance through repression of PTEN and BAK1, respectively 39,40 ; overexpression of let-7i giving rise to an increase in cisplatin sensitivity 41 and dysregulation of miR-106a, miR-591 and miR-200c conferring paclitaxel resistance to cells by targeting BCL10 and caspase-7, ZEB1 and TUBB3. 5,42 These findings indicated that studies of miRNAs that target MDRrelated proteins would undoubtedly shed light on the therapeutic value of miRNAs in cancer.…”

Section: Discussionmentioning

confidence: 99%

Expression of Concern: miR‐145 sensitizes ovarian cancer cells to paclitaxel by targeting Sp1 and Cdk6

Zhu

Xie

et al. 2014

Intl Journal of Cancer

102

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Multidrug resistance (MDR) remains a major obstacle to effective chemotherapy treatment in ovarian cancer. In our study, paclitaxel-resistant ovarian cancer patients and cell lines had decreased miR-145 levels and expressed high levels of Sp1 and Cdk6. Introducing miR-145 into SKOV3/PTX and A2780/PTX cells led to a reduction in Cdk6 and Sp1 along with downregulation of P-gp and pRb. These changes resulted in increased accumulation of antineoplastic drugs and G1 cell cycle arrest, which rendered the cells more sensitive to paclitaxel in vitro and in vivo. These effects could be reversed by reintroducing Sp1 or Cdk6 into cells expressing high levels of miR-145, resulting in restoration of P-gp and pRb levels. Furthermore, we confirmed that both Cdk6 and Sp1 are targets of miR-145. Intriguingly, demethylation with 5-aza-dC led to reactivation of miR-145 expression in drug-resistant ovarian cancer cell lines, which also resulted in increased sensitivity to paclitaxel. Collectively, these findings begin to elucidate the role of miR-145 as an important regulator of chemoresistance in ovarian cancer by controlling both Cdk6 and Sp1.Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. Because of the absence of early symptoms, most patients are diagnosed at an advanced stage. Chemotherapy is one of the most frequently used treatment modalities for advanced-stage ovarian cancer patients. Although initial responsiveness to first-line chemotherapy consisting of a platinum-containing compound in combination with paclitaxel (PTX) is high, up to 80% of patients eventually relapse and become platinum/taxane resistant. Therefore, a better understanding of the mechanisms involved in MDR ovarian cancer and more effective therapeutic approaches are immediately required.1 Multiple mechanisms that mediate intrinsic or acquired resistance to paclitaxel have been identified. A major contributor to resistance is the active export of drugs by transmembrane polysubstrate efflux pumps that prevent drugs from reaching their intracellular targets, and a highly studied member of this family is multidrug resistance-1 (MDR1). MDR1 encodes for the membrane transporter P-glycoprotein (P-gp), whose substrates included a wide array of toxins and commonly used chemotherapeutic agents, including taxanes and anthracyclines. 2 Cell cycle dysregulation is another common molecular finding in ovarian cancer, and the cyclin-dependent kinases (Cdks) represent attractive targets in this pathway. For example, inhibition of Cdk6, one of the powerful cell cycle progression regulators, showed encouraging effects in animal experiments and clinical trials. MicroRNAs (miRNAs) are small, noncoding RNA molecules that negatively regulate a large number of proteinencoding genes via either mRNA degradation or translational silencing. Evidence is emerging for roles of miRNAs in modulating drug sensitivity/resistance of cells, 4,5 specifically for one class of miRNAs that target survival pathways or pathways that regulate apoptosis sensitivity, such ...

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Section: Discussionmentioning

confidence: 99%

Expression of Concern: miR‐145 sensitizes ovarian cancer cells to paclitaxel by targeting Sp1 and Cdk6

Zhu

Xie

et al. 2014

Intl Journal of Cancer

102

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“…During breast cancer invasion and angiogenesis, the ALK-4 mRNA is down-regulated by miR-98; because ALK-4 positively contributes to breast cancer metastasis, miR-98 acts as a metastasis suppressor (Siragam et al 2012). Finally, in ovarian cancers, the nodal/ALK-7 tumor suppressor pathway is inactivated by miR-376c, which down-regulates the ALK-7 receptor, showing that miR-376c has a protumorigenic effect (Ye et al 2011).…”

Section: Control Of Tgf-b Receptor Expression By Micrornasmentioning

confidence: 99%

Signaling Receptors for TGF-β Family Members

Heldin

Moustakas

2016

Cold Spring Harb Perspect Biol

549

498

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Transforming growth factor b (TGF-b) family members signal via heterotetrameric complexes of type I and type II dual specificity kinase receptors. The activation and stability of the receptors are controlled by posttranslational modifications, such as phosphorylation, ubiquitylation, sumoylation, and neddylation, as well as by interaction with other proteins at the cell surface and in the cytoplasm. Activation of TGF-b receptors induces signaling via formation of Smad complexes that are translocated to the nucleus where they act as transcription factors, as well as via non-Smad pathways, including the Erk1/2, JNK and p38 MAP kinase pathways, and the Src tyrosine kinase, phosphatidylinositol 3 0 -kinase, and Rho GTPases.

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“…Through binding to the 39-untranslated region (39UTR) of different target mRNAs (mRNAs), microRNAs can repress the translation of the target mRNAs (Seitz et al, 2003). As a new class of regulatory molecules, miRNAs have diverse functions in cell proliferation Viticchiè et al, 2011;Yu et al, 2012), survival (Fang et al, 2012a;Ye et al, 2011), invasion Luo et al, 2012;Siragam et al, 2012), cell differentiation (Goljanek-Whysall et al, 2012;Kahai et al, 2009;Rutnam and Yang, 2012b), morphogenesis (Wang et al, 2008a), tissue growth (Shan et al, 2009), angiogenesis Lee et al, 2007;Smits et al, 2010;Zou et al, 2012), tumor development (Nohata et al, 2012;Volinia et al, 2006) and metastasis (Huang et al, 2008;Ma et al, 2007;Rutnam and Yang, 2012a). The largest functional group of miRNAs is the one involved in cancer development.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA miR-24 Enhances Tumor Invasion and Metastasis by Targeting PTPN9 and PTPRF to Promote EGF Signaling

Fang

et al. 2013

Journal of Cell Science

Self Cite

126

111

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SummaryMicroRNAs are known to play regulatory roles in gene expression associated with cancer development. We analyzed levels of the microRNA miR-24 in patients with breast carcinoma and found that miR-24 was higher in breast carcinoma samples than in benign breast tissues. We generated constructs expressing miR-24 and studied its functions using both in vitro and in vivo techniques. We found that the ectopic expression of miR-24 promoted breast cancer cell invasion and migration. In vivo experiments in mice indicated that the expression of miR-24 enhanced tumor growth, invasion into local tissues, metastasis to lung tissues and decreased overall mouse survival. In the miR-24-expressing cells and tumors, EGFR was highly phosphorylated, whereas expression of the phosphatases tyrosine-protein phosphatase non-receptor type 9 (PTPN9) and receptor-type tyrosine-protein phosphatase F (PTPRF) were repressed. We confirmed that miR-24 could directly target both PTPN9 and PTPRF. Consistent with this, we found that the levels of phosphorylated epidermal growth factor receptor (pEGFR) were higher whereas the levels of PTPN9 and PTPRF were lower in the patients with metastatic breast carcinoma. Ectopic expression of PTPN9 and PTPRF decreased pEGFR levels, cell invasion, migration and tumor metastasis. Furthermore, we found that MMP2, MMP11, pErk, and ADAM15 were upregulated, whereas TIMP2 was downregulated; all of which supported the roles of miR-24 in tumor invasion and metastasis. Our results suggest that miR-24 plays a key role in breast cancer invasion and metastasis. miR-24 could potentially be a target for cancer intervention.

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MicroRNA 376c enhances ovarian cancer cell survival by targeting activin receptor-like kinase 7: implications for chemoresistance

Cited by 113 publications

References 50 publications

Expression of Concern: miR‐145 sensitizes ovarian cancer cells to paclitaxel by targeting Sp1 and Cdk6

Expression of Concern: miR‐145 sensitizes ovarian cancer cells to paclitaxel by targeting Sp1 and Cdk6

Signaling Receptors for TGF-β Family Members

MicroRNA miR-24 Enhances Tumor Invasion and Metastasis by Targeting PTPN9 and PTPRF to Promote EGF Signaling

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