Role of miRNA gene expression in induction of EMT in NSCLC

Grants and Contracts Details


Adenocarcinomas of the lung are frequently metastatic and thus lethal. Researchers long hypothesized that macrophages (mö) can induce a tumor to gain metastatic potential (Pollard, 2004). We postulate that signals from M2-like polarized mö or tumor-associated mö (TAMs) can induce a gene expression program in the tumor that influences epithelial-to-mesenchymal transition (EMT), invasion, and metastasis. Further, we believe that expression of specific microRNA (miRNA) genes in the tumor genome is the initial response to signaling from the immune cell component of the tumor microenvironment. The resulting transcriptional program is characterized by activation of EMT-specific transcription factors Zeb1/2, Snail, Slug and Twist and reduced expression of E-cadherin. We identified a 13-gene miRNA signature of response of lung adenocarcinoma cells to the EGFR-inhibitor, erlotinib (Bryant, et al., submitted). The signature is rich in miRNAs involved in EMT. Importantly, the 13 genes can also differentiate primary from metastatic tumor tissue using clustering methods. Further, we have shown that treatment of A549 lung adenocarcinoma cells and immortalized bronchial epithelial cells (Beas2B) with recombinant TGFâ1, an inducer of EMT, can alter the expression profile of several of the 13 miRNA signature genes, induce Zeb1 and Snail expression, and reduce E-cadherin. Thus, we believe that signaling from the host immune response to the tumor may initiate a program of miRNA gene expression necessary for induction of EMT and loss of sensitivity to EGFR inhibition that may be dependent on TGFâ. Therefore, by identifying mRNA targets of the 13 miRNAs and by discerning the role of TGFâ signaling on expression of the 13 gene signature, new targets for inhibitory therapeutics may be identified or modulators of TGFâ signaling may be used as intervention therapy to prevent tumor metastasis and lessen the severity of disease.
Effective start/end date11/1/1110/31/12


  • Lung Cancer Research Foundation: $50,000.00


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