miR‐137 inhibits the proliferation of lung cancer cells by targeting Cdc42 and Cdk6

Zhu, Xiaolan; Li, Yuefeng; Shen, Huiling; Li, Hao; Long, Lingliang; Hui, Lulu; Xu, Wenlin

doi:10.1016/j.febslet.2012.11.004

Cited by 151 publications

(114 citation statements)

References 39 publications

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“…As previously described, 36 proteins from cells or tissues were separated by dodecyl sulfate, sodium salt-Polyacrylamide gel electrophoresis (SDS-PAGE) and then transferred to polyvinylidene difluoride membranes (Bio-Rad, CA, USA). The membranes were blocked and then probed with antibodies against Sp1 (sc-420), Cdk6 (sc-177), P-gp (sc-55510), Cyclin D1 (sc-753), vascular endothelial growth factor (VEGF) (sc-152) (Santa Cruz Biotechnology), pRb (R3403) or b-actin (A9044, Sigma, St. Louis, MO).…”

Section: Western Blot Assaymentioning

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

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104

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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: Western Blot Assaymentioning

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

Self Cite

104

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“…miRNAs are endogenous non-coding 19-23 nucleotide long RNA molecules that are located on chromosome 1p22. It has been revealed that miRNAs can downregulate gene expression by binding to the 3' untranslated regions (3'UTRs) of mRNA (6), thus affecting the proliferation, and metastasis of numerous types of cancer, such as gastric (7), breast (8) and lung cancer (9,10). The expression of miR-137 has been identified to be significantly downregulated in lung cancer compared with healthy lung tissue (11).…”

Section: Introductionmentioning

confidence: 99%

“…Notably, the downregulation of miR-137 in lung cancer cells may be rescued following treatment with a DNA methylation inhibitor. Furthermore, miR-137 has a tumor suppressor function by directly targeting cell division cycle 42 (CDC42) mRNA to inhibit the proliferation and invasion of colorectal cancer cells (10). miR-137 has been revealed to be upregulated following preoperative capecitabine chemoradiotherapy in rectal cancer.…”

Section: Introductionmentioning

confidence: 99%

miR-137 inhibits the proliferation of human non-small cell lung cancer cells by targeting SRC3

Chen

Zhang

et al. 2017

Oncology Letters

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Abstract. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. The results of the present study demonstrate that high expression of microRNA (miR)-137 and low expression of steroid receptor coactivator-3 (SRC3) had a significant negative correlation in 40 NSCLC tissue samples. In addition, cell colony formation and proliferation was significantly reduced in miR-137-transfected A549 and NCI-H838 cells compared with scramble-transfected NSCLC cell lines. miR-137 was identified to induce G 1 /S cell cycle arrest and dysregulate the mRNA expression of cell cycle-associated proteins (proliferating cell nuclear antigen, cyclin E, cyclin A1, cyclin A2 and p21) in NSCLC cells. Notably, miR-137 could significantly suppress SRC3 3' untranslated region (UTR) luciferase-reporter activity, an effect that was not detectable when the putative 3'-UTR target-site was mutated, further clarifying the molecular mechanisms underlying the role of miR-137 in NSCLC. In conclusion, the results of the present study suggest that miR-137 suppresses NSCLC cell proliferation by partially targeting SRC3.

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“…46 Blockage of CDK6 expression by microRNAs (miRNAs) has been shown to inhibit the proliferation of gliomas, medulloblastoma, prostate, bladder, gastric, hepatocellular, and lung cancer cells, indicating the significant role of CDK6 in the initiation and progression of these cancers. [51][52][53][54][55][56][57][58] These observations, coupled with the fact that mice lacking D-type cyclins and/or CDK4/6 are viable, make targeting components of the CDK4/6 cyclin D-INK4-pRb-E2F pathway a highly attractive anti-cancer strategy. 12,14 CDK6 and hematological malignancies Acute myeloid leukemia (AML) is a malignant transformation of hematopoietic cells characterized by an increase in the number of myeloid cells in the marrow and an arrest in their maturation.…”

Section: Introductionmentioning

confidence: 99%

Targeting CDK6 in cancer: State of the art and new insights

et al. 2015

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Cyclin-dependent kinase 6 (CDK6) plays a vital role in regulating the progression of the cell cycle. More recently, CDK6 has also been shown to have a transcriptional role in tumor angiogenesis. Up-regulated CDK6 activity is associated with the development of several types of cancers. While CDK6 is over-expressed in cancer cells, it has a low detectable level in non-cancerous cells and CDK6-null mice develop normally, suggesting a specific oncogenic role of CDK6, and that its inhibition may represent an ideal mechanism-based and low toxic therapeutic strategy in cancer treatment. Identification of selective small molecule inhibitors of CDK6 is thus needed for drug development. Herein, we review the latest understandings of the biological regulation and oncogenic roles of CDK6. The potential clinical relevance of CDK6 inhibition, the progress in the development of small-molecule CDK6 inhibitors and the rational design of potential selective CDK6 inhibitors are also discussed.

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miR‐137 inhibits the proliferation of lung cancer cells by targeting Cdc42 and Cdk6

Cited by 151 publications

References 39 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

miR-137 inhibits the proliferation of human non-small cell lung cancer cells by targeting SRC3

Targeting CDK6 in cancer: State of the art and new insights

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