Dual-strand tumor-suppressor microRNA-145 (miR-145-5p and miR-145-3p) coordinately targeted MTDH in lung squamous cell carcinoma

Abstract

Patients with lung adenocarcinoma may benefit from recently developed molecular targeted therapies. However, analogous advanced treatments are not available for patients with lung squamous cell carcinoma (lung SCC). The survival rate of patients with the advanced stage of lung SCC remains poor. Exploration of novel lung SCC oncogenic pathways might lead to new treatment protocols for the disease. Based on this concept, we have identified microRNA-(miRNA) mediated oncogenic pathways in lung SCC. It is well known that miR-145-5p (the guide strand) functions as a tumor suppressor in several types of cancer. However, the impact of miR-145-3p (the passenger strand) on cancer cells is still ambiguous. Expression levels of miR-145-5p and miR-145-3p were markedly reduced in cancer tissues, and ectopic expression of these miRNAs inhibited cancer cell aggressiveness, suggesting that both miR-145-3p as well as miR-145-5p acted as antitumor miRNAs. We identified seven putative target genes (MTDH, EPN3, TPD52, CYP27B1, LMAN1, STAT1 and TXNDC12) that were coordinately regulated by miR-145-5p and miR-145-3p in lung SCC. Among the seven genes, we found that metadherin (MTDH) was a direct target of these miRNAs. Kaplan-Meier survival curves showed that high expression of MTDH predicted reduced survival of lung SCC patients. We investigated pathways downstream from MTDH by using genome-wide gene expression analysis. Our data showed that several anti-apoptosis and pro-proliferation genes were involved in pathways downstream from MTDH in lung SCC. Taken together, both strands of miR-145, miR-145-5p and miR-145-3p are functional and play pivotal roles as antitumor miRNAs in lung SCC.

Involvement of dual‐strand of the miR‐144 duplex and their targets in the pathogenesis of lung squamous cell carcinoma

“…After cotransfecting miRNA and the constructed vector into EBC‐1 and SK‐MES‐1 cells, firefly and Renilla luciferase activities were measured using a dual Luciferase assay kit (Promega). The procedure was described previously …”

“…Through our continuing work, we have identified antitumor miRNAs and their target oncogenic genes in LUSQ . Moreover, detailed analyses of our original miRNA expression signatures by RNA sequencing have revealed that passenger strands of miRNAs actually act as antitumor miRNAs and are involved in cancer pathogenesis .…”

Role of Nerve Growth Factor (NGF) and miRNAs in Epithelial Ovarian Cancer

“…Most studies about miR-145 are focused on miR-145-5p, which is defined as the mature strand, while miR-145-3p is the passenger strand. Interestingly, it has recently been reported that both of these miRs could have biological activity, and it is very rare to find duplex miRs where both strands have biological functions [132]. miR-23b belongs to the miR-23b/27b/24 cluster, it has been described as a tumor suppressor, and some miR-23b targets include cyclin G1 [133] and the transcription factor RUNX2, involved in cellular survival, migration and invasion [134].…”

Molecular pathogenesis of pancreatic ductal adenocarcinoma: Impact of passenger strand of pre‐miR‐148a on gene regulation

“…For example, miR‐145‐3p (passenger strand) was significantly downregulated in castration‐resistant prostate cancer and restoration of miR‐145‐3p inhibited cancer cell migration and invasion through targeting of MELK , NCAPG , BUB1 , and CDK1 . Similarly, antitumor functions have also been shown in bladder cancer and lung cancer . Realization that the passenger strand of miRNA is involved in the regulation of RNA networks will improve our understanding of cancer cell development and tumor progression.…”