KRAS induces lung tumorigenesis through microRNAs modulation

Abstract

Oncogenic KRAS induces tumor onset and development by modulating gene expression via different molecular mechanisms. MicroRNAs (miRNAs) are small non-coding RNAs that have been established as main players in tumorigenesis. By overexpressing wild type or mutant KRAS (KRASG12D) and using inducible human and mouse cell lines, we analyzed KRAS-regulated microRNAs in non-small-cell lung cancer (NSCLC). We show that miR-30c and miR-21 are significantly upregulated by both KRAS isoforms and induce drug resistance and enhance cell migration/invasion via inhibiting crucial tumor suppressor genes, such as NF1, RASA1, BID, and RASSF8. MiR-30c and miR-21 levels were significantly elevated in tumors from patients that underwent surgical resection of early stages NSCLC compared to normal lung and in plasma from the same patients. Systemic delivery of LNA-anti-miR-21 in combination with cisplatin in vivo completely suppressed the development of lung tumors in a mouse model of lung cancer. Mechanistically, we demonstrated that ELK1 is responsible for miR-30c and miR-21 transcriptional activation by direct binding to the miRNA proximal promoter regions. In summary, our study defines that miR-30c and miR-21 may be valid biomarkers for early NSCLC detection and their silencing could be beneficial for therapeutic applications.

The Mir181ab1 cluster promotes KRAS-driven oncogenesis and progression in lung and pancreas

“…Although alterations such as gene amplification, deletion, and translocation are common events in genomic regions hosting miRNAs and can influence their expression in cancer (66), direct regulation by oncogenes and tumor suppressors can also significantly influence miRNA expression levels (27)(28)(29)(30)(31). Previous studies have suggested upregulation and functional roles for miR21, miR450b-5p, and miR30c in response to oncogenic KRAS in cancer (14)(15)(16)(17). Here we used primary MEFs with conditional expression of oncogenic KRAS (36) to identify key dysregulated miRNAs.…”

“…An alternative mechanism for regulation of gene expression is via microRNAs (miRNAs) (13). However, our understanding of the role of miRNAs functionally regulating the consequences of KRAS activation is still limited (14)(15)(16)(17). The study of miRNA function is an alternative strategy to yield molecular insights necessary for the development of novel therapies against KRAS-driven tumors.…”

Non-Coding RNAs in Lung Tumor Initiation and Progression

“…The interplay between miRNA and ROS in cancer treatment response has been discussed in recent reviews [256,257]. Non-coding RNAs such as miR-21 and miR-30c have shown upregulation with KRAS G12D overexpression, which as a result enhance regulation of Ras downstream pathways [207]. In contrast, a negative regulator of Ras includes the let-7 family which acts as a tumor suppressive miRNA and inhibits downstream signaling [104].…”

Role of RASA1 in cancer: A review and update (Review)

“…Zhu et al revealed that hsa-miR-182 downregulated RASA1 to suppress proliferation of lung squamous cell carcinoma through tissue microarray and quantitative PCR ( 60 ). Recently, Shi et al demonstrated that miR-30c and miR-21 were significantly upregulated by two KRAS isoforms in small-cell lung cancer and induced drug resistance by inhibiting key tumour suppressor genes such as neurofibromatosis type one (NF1), RASA1, BID, and RASSF8 ( 61 ). Mutations of EGFR result in drug resistance and relapse in patients with non-small cell lung cancer (NSCLC) ( 62 ).…”