MicroRNA-520g Confers Drug Resistance by Regulating p21 Expression in Colorectal Cancer

Zhang, Yang; Geng, Li; Talmon, Geoffrey A.; Wang, Jing

doi:10.1074/jbc.m114.620252

Cited by 91 publications

(71 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One week after injection, 5-FU (25 mg/kg/day) or carrier was administered by i.p. injection for 5 consecutive days/week for 2 weeks (26,27). Tumor volumes were measured at the beginning of the treatment and every other day afterward until the mice were euthanized.…”

Section: Methodsmentioning

confidence: 99%

“…A 5-FU dose of 25 mg/kg/day was used because the control tumors showed little response to this dose, which would provide a good window to observe enhanced drug efficacy in vivo by knockdown of PDK4 expression. The treatment was for 5 consecutive days/week for 2 weeks (26,27). Throughout the treatment, the weight of the mice remained stable.…”

Section: Knockdown Of Pdk4 Expression Increases the Efficiency Of 5-fmentioning

confidence: 99%

See 1 more Smart Citation

Transforming Growth Factor β Mediates Drug Resistance by Regulating the Expression of Pyruvate Dehydrogenase Kinase 4 in Colorectal Cancer

Zhang¹,

Zhang

Geng³

et al. 2016

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Drug resistance is one of the main causes of colon cancer recurrence. However, our understanding of the underlying mechanisms and availability of therapeutic options remains limited. Here we show that expression of pyruvate dehydrogenase kinase 4 (PDK4) is positively correlated with drug resistance of colon cancer cells and induced by 5-fluorouracil (5-FU) treatment in drug-resistant but not drug-sensitive cells. Knockdown of PDK4 expression sensitizes colon cancer cells to 5-FU or oxaliplatin-induced apoptosis in vitro and increases the effectiveness of 5-FU in the inhibition of tumor growth in a mouse xenograft model in vivo. In addition, we demonstrate for the first time that TGF␤ mediates drug resistance by regulating PDK4 expression and that 5-FU induces PDK4 expression in a TGF␤ signaling-dependent manner. Mechanistically, knockdown or inhibition of PDK4 significantly increases the inhibitory effect of 5-FU on expression of the anti-apoptotic factors Bcl-2 and survivin. Importantly, studies of patient samples indicate that expression of PDK4 and phosphorylation of Smad2, an indicator of TGF␤ pathway activation, show a strong correlation and that both positively associate with chemoresistance in colorectal cancer. These findings indicate that the TGF␤/PDK4 signaling axis plays an important role in the response of colorectal cancer to chemotherapy. A major implication of our studies is that inhibition of PDK4 may have considerable therapeutic potential to overcome drug resistance in colorectal cancer patients, which warrants the development of PDK4-specific inhibitors.Colorectal cancer is the third most common cancer diagnosed and the second leading cause of cancer mortality in the United States. In addition to surgery, treatment for colorectal cancer patients, especially for patients with advanced disease, primarily relies on chemotherapy and radiation therapy. 5 is one of the most commonly used chemotherapeutic agents for colorectal cancer treatment. It induces cell cycle arrest and apoptosis in cancer cells (1). Although adjuvant 5-FU treatment has a good success rate, the high recurrence is still a major hurdle of treating colorectal cancer because of the resistance to chemotherapeutic drugs. Therefore, it is important to understand the mechanisms of drug resistance and identify new targets to increase the effectiveness of chemotherapy in colorectal cancer. TGF␤ plays an important role in cancer development and progression. Upon ligand binding, TGF␤ type II receptor (RII) recruits and activates TGF␤ type I receptor (RI), which then activates Smad2 and Smad3. Activated Smad2 and Smad3 form complexes with Smad4 and translocate to the nucleus, where they regulate gene expression (2). We and others have demonstrated that TGF␤ suppresses tumorigenicity in a variety of cancers, including colorectal cancer, and that loss of TGF␤ signaling leads to malignancy (3-6). Although many studies have shown that TGF␤ promotes metastasis (7), others have demonstrated that TGF␤ suppresses metastasis (8,9). Recently, studi...

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Knockdown Of Pdk4 Expression Increases the Efficiency Of 5-fmentioning

confidence: 99%

Transforming Growth Factor β Mediates Drug Resistance by Regulating the Expression of Pyruvate Dehydrogenase Kinase 4 in Colorectal Cancer

Zhang¹,

Zhang

Geng³

et al. 2016

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…For instance, miR-133a and miR-326 are involved in adriamycin resistance in HepG2 cells through altering expression of multidrug resistance-associated protein 1 (ABCC1) [33]. Moreover, p53 suppresses miR-520 g expression, which mediates drug resistance through down-regulation of p21 [34]. Inhibition of miR-9 results in decreased sensitivity to cisplatin in primary epithelial ovarian cancer cells [35].…”

Section: Discussionmentioning

confidence: 99%

miR-17-5p down-regulation contributes to erlotinib resistance in non-small cell lung cancer cells

Zhang

Lin

Wang

et al. 2016

Journal of Drug Targeting

View full text Add to dashboard Cite

Non-small cell lung cancer (NSCLC) is the major cause of lung cancer-related deaths. Erlotinib is an effective drug for NSCLC patients, but its effect in advanced NSCLC is compromised because of the drug resistance. The mechanism of erlotinib resistance in NSCLC is largely unknown. In the current study, we found that erlotinib treatment down-regulated miR-17-5p level in A549 cells and miR-17-5p was lower in acquired erlotinib-resistant A549 cells (A549-ER) compared with erlotinib-sensitive A549 cells. Consistently, miR-17-5p was down-regulated in the tumor tissues and the plasma of erlotinib-resistant NSCLC patients in comparison to those who are sensitive to erlotinib. Moreover, miR-17-5p mimic increased the sensitivity of A549 and A549-ER to erlotinib. In contrast, miR-17-5p inhibitor decreased the cell death of A549 and A549-ER induced by erlotinib. In addition, we also demonstrated that miR-17-5p could inhibit the mRNA and protein levels of enhancer of zeste homolog (EZH) 1, a member of the EZH family that contributes to drug resistance in several types of cancer. The luciferase assay of 3 0 -untranslated region (UTR) demonstrates that EZH1 is a direct target of miR-17-5p and EZH1 RNAi recapitulates the effect of miR-17-5p overexpression on erlotinib resistance. Further, mutation in seed sequence of miR-17-5p could totally abolish the sensitization of A549-ER to erlotinib induced by miR-17-5p overexpression. Our results indicate that miR-17-5p down-regulation contributes to erlotinib resistance of NSCLC by modulating its target genes such as EZH1 and plasma miR-17-5p might be a potential biomarker of erlotinib response in NSCLC patients. ARTICLE HISTORY

show abstract

“…36 Moreover, miR-106b induced cell radioresistance, and miR-520g conferred drug resistance in colorectal cancer both by regulating p21 expression. 39,40 And, miR-224 promoted the chemoresistance of A549 cells to cisplatin by targeting p21 as well. 41 Our data that miR-33b-3p attenuated the cisplatin sensitivity of A549 cells by direct diminishing the p21 expression, was in consistent with above published literatures.…”

Section: Discussionmentioning

confidence: 99%

DNA damage responsive miR-33b-3p promoted lung cancer cells survival and cisplatin resistance by targeting p21^WAF1/CIP1

Huang

Chen

et al. 2016

Cell Cycle

View full text Add to dashboard Cite

Cisplatin is the most potent and widespread used chemotherapy drug for lung cancer treatment. However, the development of resistance to cisplatin is a major obstacle in clinical therapy. The principal mechanism of cisplatin is the induction of DNA damage, thus the capability of DNA damage response (DDR) is a key factor that influences the cisplatin sensitivity of cancer cells. Recent advances have demonstrated that miRNAs (microRNAs) exerted critical roles in DNA damage response; nonetheless, the association between DNA damage responsive miRNAs and cisplatin resistance and its underlying molecular mechanism still require further investigation. The present study has attempted to identify differentially expressed miRNAs in cisplatin induced DNA damage response in lung cancer cells, and probe into the effects of the misexpressed miRNAs on cisplatin sensitivity. Deep sequencing showed that miR-33b-3p was dramatically down-regulated in cisplatin-induced DNA damage response in A549 cells; and ectopic expression of miR33b-3p endowed the lung cancer cells with enhanced survival and decreased gH2A.X expression level under cisplatin treatment. Consistently, silencing of miR-33b-3p in the cisplatin-resistant A549/DDP cells evidently sensitized the cells to cisplatin. Furthermore, we identified CDKN1A (p21) as a functional target of miR-33b-3p, a critical regulator of G1/S checkpoint, which potentially mediated the protection effects of miR-33b-3p against cisplatin. In aggregate, our results suggested that miR-33b-3p modulated the cisplatin sensitivity of cancer cells might probably through impairing the DNA damage response. And the knowledge of the drug resistance conferred by miR-33b-3p has great clinical implications for improving the efficacy of chemotherapies for treating lung cancers.

show abstract

MicroRNA-520g Confers Drug Resistance by Regulating p21 Expression in Colorectal Cancer

Cited by 91 publications

References 45 publications

Transforming Growth Factor β Mediates Drug Resistance by Regulating the Expression of Pyruvate Dehydrogenase Kinase 4 in Colorectal Cancer

Transforming Growth Factor β Mediates Drug Resistance by Regulating the Expression of Pyruvate Dehydrogenase Kinase 4 in Colorectal Cancer

miR-17-5p down-regulation contributes to erlotinib resistance in non-small cell lung cancer cells

DNA damage responsive miR-33b-3p promoted lung cancer cells survival and cisplatin resistance by targeting p21^WAF1/CIP1

Contact Info

Product

Resources

About

MicroRNA-520g Confers Drug Resistance by Regulating p21 Expression in Colorectal Cancer

Cited by 91 publications

References 45 publications

Transforming Growth Factor β Mediates Drug Resistance by Regulating the Expression of Pyruvate Dehydrogenase Kinase 4 in Colorectal Cancer

Transforming Growth Factor β Mediates Drug Resistance by Regulating the Expression of Pyruvate Dehydrogenase Kinase 4 in Colorectal Cancer

miR-17-5p down-regulation contributes to erlotinib resistance in non-small cell lung cancer cells

DNA damage responsive miR-33b-3p promoted lung cancer cells survival and cisplatin resistance by targeting p21WAF1/CIP1

Contact Info

Product

Resources

About

DNA damage responsive miR-33b-3p promoted lung cancer cells survival and cisplatin resistance by targeting p21^WAF1/CIP1