A microRNA gene expression signature predicts response to erlotinib in epithelial cancer cell lines and targets EMT

Bryant, J L; Britson, Joel S.; Balko, Justin M.; Willian, M; Timmons, Ruben Berrocal; Frolov, Andrey; Black, Esther P.

doi:10.1038/bjc.2011.465

Cited by 73 publications

(53 citation statements)

References 34 publications

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“…As cited before, miR-205 posttranscriptionally represses ERBB3. Interestingly, recent results suggest that tumor cell lines sensitive to erlotinib show high levels of miR-205 and other miRNAs (41), which supports our predictions. According to our model analysis, tumor cells with E2F1 overexpression and miR-205 downregulation do not show cytostatic drug resistance, but synergy with high ERBB3 gene activation is required to acquire this feature.…”

Section: Discussionsupporting

confidence: 80%

Kinetic Modeling–Based Detection of Genetic Signatures That Provide Chemoresistance via the E2F1-p73/DNp73-miR-205 Network

et al. 2013

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Drug resistance is a major cause of deaths from cancer. E2F1 is a transcription factor involved in cell proliferation, apoptosis. and metastasis through an intricate regulatory network, which includes other transcription factors like p73 and cancer-related microRNAs like miR-205. To investigate the emergence of drug resistance, we developed a methodology that integrates experimental data with a network biology and kinetic modeling. Using a regulatory map developed to summarize knowledge on E2F1 and its interplay with p73/ DNp73 and miR-205 in cancer drug responses, we derived a kinetic model that represents the network response to certain genotoxic and cytostatic anticancer drugs. By perturbing the model parameters, we simulated heterogeneous cell configurations referred to as in silico cell lines. These were used to detect genetic signatures characteristic for single or double drug resistance. We identified a signature composed of high E2F1 and low miR-205 expression that promotes resistance to genotoxic drugs. In this signature, downregulation of miR-205, can be mediated by an imbalance in the p73/DNp73 ratio or by dysregulation of other cancer-related regulators of miR-205 expression such as TGFb-1 or TWIST1. In addition, we found that a genetic signature composed of high E2F1, low miR-205, and high ERBB3 can render tumor cells insensitive to both cytostatic and genotoxic drugs. Our model simulations also suggested that conventional genotoxic drug treatment favors selection of chemoresistant cells in genetically heterogeneous tumors, in a manner requiring dysregulation of incoherent feedforward loops that involve E2F1, p73/DNp73, and miR-205. Cancer Res; 73(12); 3511-24. Ó2013 AACR.

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Section: Discussionsupporting

confidence: 80%

Kinetic Modeling–Based Detection of Genetic Signatures That Provide Chemoresistance via the E2F1-p73/DNp73-miR-205 Network

et al. 2013

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“…Furthermore, a TGF-β1-responsive element is identified at the promoter region of miR-200c, which suggests the suppression of miR-200c in a Smad3/4-dependent manner at the downstream of activated TGF-β signaling. Interestingly, TGF-β1 is also not able to fully induce EMT and to cause significant changes in erlotinib response in these cells [86]. Therefore, further understanding of the effects of TGF-β signaling on miR-200c-mediated EMT and anti-EGFR resistance could provide more details about the importance of the tumor microenvironment in controlling miRNA expression and response to targeted therapies.…”

Section: Mir-200c Emt and Targeted Therapy Resistancementioning

confidence: 99%

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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“…These miRNAs, in particular miR-140-3p, miR-628-5p, miR-518f, miR-636, miR-301a, miR-34c, miR-224, miR-197, miR-205, miR135b, miR-200b, miR-200c, and miR-141, regulate proteins that are potentially involved in epithelial-to-mesenchymal transition (EMT). Interestingly, treatment with TGFβ1 modulated the expression of these miRNAs and EMT proteins and, for this reason, they hypothesized that the tumor microenvironment elicits TGFβ1 and promotes a miRNA expression pattern that induces resistance to anti-EGFR and favors the induction of EMT, invasion, and metastasis in lung cancer cells [107]. A pivotal study reported that miR-30b, miR30c, miR-221 and miR-222 are regulated by both EGF and MET receptors, while miR-103 and miR-203 are modulated only by MET.…”

Section: Mirnas and Resistance To Targeted Therapy In Nsclcmentioning

confidence: 99%

Impact of microRNAs in Resistance to Chemotherapy and Novel Targeted Agents in Non-Small Cell Lung Cancer

Rolfo¹,

Fanale²,

Hong³

et al. 2014

CPB

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Despite recent advances in understanding the cancer signaling pathways and in developing new therapeutic strategies, non-small cell lung cancer (NSCLC) shows grim prognosis and high incidence of recurrence. Insufficient disruption of oncogenic signaling and drug resistance are the most common causes of tumor recurrence. Drug resistance, intrinsic or acquired, represents a main obstacle in NSCLC therapeutics by limiting the efficacy both of conventional chemotherapeutic compounds and new targeted agents. Therefore, novel and more innovative approaches are required for treatment of this tumor. MicroRNAs (miRNAs) are a family of small non-coding RNAs that regulate gene expression by sequence-specific targeting of mRNAs causing mRNA degradation or translational repression. Accumulating evidence suggests that impairment of candidate miRNAs may be involved in the acquisition of tumor cell resistance to conventional chemotherapy and novel biological agents by affecting the drug sensitivity of cancer cells. The modulation of these miRNAs, using antagomiRs or miRNA mimics, can restore key gene networks and signaling pathways, and optimize anticancer therapies by inhibition of tumor cell proliferation and increasing the drug sensitivity. Therefore, miRNA-based therapeutics provides an attractive anti-tumor approach for developing new and more effective individualized therapeutic strategies, improving drug efficiency, and for predicting the response to different anticancer drugs. In this review, we present an overview on the role of miRNAs in resistance mechanisms of NSCLC, discussing the main studies on the aberrations in apoptosis, cell cycle and DNA damage repair pathways, as well as in novel drug targets.

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A microRNA gene expression signature predicts response to erlotinib in epithelial cancer cell lines and targets EMT

Cited by 73 publications

References 34 publications

Kinetic Modeling–Based Detection of Genetic Signatures That Provide Chemoresistance via the E2F1-p73/DNp73-miR-205 Network

Kinetic Modeling–Based Detection of Genetic Signatures That Provide Chemoresistance via the E2F1-p73/DNp73-miR-205 Network

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

Impact of microRNAs in Resistance to Chemotherapy and Novel Targeted Agents in Non-Small Cell Lung Cancer

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