MicroRNA-214 Regulates the Acquired Resistance to Gefitinib via the PTEN/AKT Pathway in EGFR-mutant Cell Lines

Wang, Yongsheng; Wang, Yinhua; Xia, Hongping; Zhou, Shunhua; Schmid-Bindert, Gerald; Zhou, Caicun

doi:10.7314/apjcp.2012.13.1.255

Cited by 104 publications

(60 citation statements)

References 40 publications

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“…Silencing PTEN expression may promote cell proliferation, decrease the rate of apoptosis of HCC827 cells and reduce the sensitivity of HCC827 cells to icotinib. The current study hypothesized that the underlying mechanisms may involve the loss of PTEN with an increasing PIP-3 concentration, the hyperactivation of Akt and the subsequent release of cytochrome c and the inactivation of forkhead, caspase-9 and B-cell-lymphoma-2 associated agonist of cell death (26). PTEN may influence cell proliferation and apoptosis by regulating the MAPK signaling pathway and the extracellular signal-regulated protein kinase cell survival pathway (22,27,28).…”

Section: Discussionmentioning

confidence: 99%

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Reduced expression levels of PTEN are associated with decreased sensitivity of HCC827 cells to icotinib

Zhai¹,

Zhang²,

Kang

et al. 2017

Oncology Letters

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Abstract. The clinical resistance of non-small cell lung cancer (NSCLC) to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has been linked to EGFR T790M resistance mutations or MET amplifications. Additional mechanisms underlying EGFR-TKI drug resistance remain unclear. The present study demonstrated that icotinib significantly inhibited the proliferation and increased the apoptosis rate of HCC827 cells; the cellular mRNA and protein expression levels of phosphatase and tensin homolog (PTEN) were also significantly downregulated. To investigate the effect of PTEN expression levels on the sensitivity of HCC827 cells to icotinib, PTEN expression was silenced using a PTEN-specific small interfering RNA. The current study identified that the downregulation of PTEN expression levels may promote cellular proliferation in addition to decreasing the apoptosis of HCC827 cells, and may reduce the sensitivity of HCC827 cells to icotinib. These results suggested that reduced PTEN expression levels were associated with the decreased sensitivity of HCC827 cells to icotinib. Furthermore, PTEN expression levels may be a useful marker for predicting icotinib resistance and elucidating the resistance mechanisms underlying EGFR-mutated NSCLC.

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Section: Discussionmentioning

confidence: 99%

“…Loss of PTEN is involved in the development of EGFR inhibitor resistance in certain tumor cell lines (23,24) and in patients with glioblastoma (25). The underlying mechanisms may include promoter hypermethylation, post-translational modifications or the alternative splicing of the pre-mRNA (26).…”

Section: Discussionmentioning

confidence: 99%

Reduced expression levels of PTEN are associated with decreased sensitivity of HCC827 cells to icotinib

Zhai¹,

Zhang²,

Kang

et al. 2017

Oncology Letters

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“…resistant cell line, showed a relevant up-regulation of miR-214 and the knockdown of miR-214 altered the expression levels of PTEN and p-Akt, and re-sensitized HCC827/GR to gefitinib [104]. The activation of both p-Akt and ERK can be regulated by miR-126, whose overexpression inhibits the cell proliferation and significantly enhances the cytotoxicity induced by gefitinib in H460 and A549 cells.…”

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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“…Incidence of drug resistance due to mutation in signaling molecules have indeed been reported. For example, cells expressing EGFR with activating site mutation has been found to confer resistance to gefitinib, an inhibitor of EGFR's tyrosine kinase domain (Greulich et al, 2005;Wang et al, 2012). It is possible that the E322K-ERK2 mutant, which also remains constitutively active similar to the above EGFR mutant, may similarly display resistance to inhibitors of EGFR and MEK.…”

Section: Discussionmentioning

confidence: 99%

Common Docking Domain Mutation E322K of the ERK2 Gene is Infrequent in Oral Squamous Cell Carcinomas

Valiathan

Thenumgal²,

Jayaraman³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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Background: Mutations in the MAPK (Mitogen Activated Protein Kinase) signaling pathway -EGFR/Ras/ RAF/MEK have been associated with the development of several carcinomas. ERK2, a downstream target of the MAPK pathway and a founding member of the MAPK family is activated by cellular signals emanating at the cell membrane. Activated ERK2 translocates into the nucleus to transactivate genes that promote cell proliferation. MKP -a dual specific phosphatase -interacts with activated ERK2 via the common docking (CD) domain of the later to inactivate (dephosphorylate) and effectively terminate further cell proliferation. A constitutively active form of ERK2 carrying a single point mutation -E322K in its CD domain, was earlier reported by our laboratory. In the present study, we investigated the prevalence of this CD domain E322K mutation in 88 well differentiated OSCC tissue samples. Materials and Method: Genomic DNA specimens isolated from 88 oral squamous cell carcinoma tissue samples were amplified with primers flanking the CD domain of the ERK2 gene. Subsequently, PCR amplicons were gel purified and subjected to direct sequencing to screen for mutations. Results: Direct sequencing of eighty eight OSCC samples identified an E322K CD domain mutation in only one (1.1%) OSCC sample. Conclusions: Our result indicates that mutation in the CD domain of ERK2 is rare in OSCC patients, which suggests the role of genetic alterations in other mitogenic genes in the development of carcinoma in the rest of the patients. Nevertheless, the finding is clinically significant, as the relatively rare prevalence of the E322K mutation in OSCC suggests that ERK2, being a common end point signal in the multi-hierarchical mitogen activated signaling pathway may be explored as a viable drug target in the treatment of OSCC.

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MicroRNA-214 Regulates the Acquired Resistance to Gefitinib via the PTEN/AKT Pathway in EGFR-mutant Cell Lines

Cited by 104 publications

References 40 publications

Reduced expression levels of PTEN are associated with decreased sensitivity of HCC827 cells to icotinib

Reduced expression levels of PTEN are associated with decreased sensitivity of HCC827 cells to icotinib

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

Common Docking Domain Mutation E322K of the ERK2 Gene is Infrequent in Oral Squamous Cell Carcinomas

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