MiR-34a and miR-34b/c have distinct effects on the suppression of lung adenocarcinomas

Abstract

Three miR-34 family members (miR-34a, miR-34b, and miR-34c) are clustered on two different chromosomal loci, Mir34a and Mir34b/c. These miRNAs have identical seed sequences, which are predicted to target the same set of genes. However, miR-34a and miR-34c have different sets of negatively correlated genes in lung adenocarcinoma data from The Cancer Genome Atlas. Therefore, we hypothesized that the individual miR-34 family members, which are tumor suppressive miRNAs, would have varying effects on lung tumorigenesis. To show this, we overexpressed each miR-34 cluster in murine lung cancer cells. MiR-34b/c enhanced cancer cell attachment and suppressed cell growth and invasion compared with miR-34a. In a syngeneic mouse model, both miR-34a and miR-34b/c blocked lung metastasis. However, miR-34b/c suppressed tumor growth more than miR-34a. MiR-34b/c also decreased the expression of mesenchymal markers (Cdh2 and Fn1) and increased the expression of epithelial markers (Cldn3, Dsp, and miR-200) to a greater degree than miR-34a. These results imply that miR-34b and miR-34c inhibit epithelial-to-mesenchymal transition. Furthermore, knockout of all three miR-34 members promoted mutant Kras-driven lung tumor progression in mice. Similarly, lung adenocarcinoma patients with higher miR-34a/b/c levels had better survival rates than did those with lower levels. In summary, we suggest that miR-34b and miR-34c are more effective tumor suppressors than miR-34a.

Increased miR‐34c mediates synaptic deficits by targeting synaptotagmin 1 through ROS‐JNK‐p53 pathway in Alzheimer’s Disease

“…MiR‐34c is an important tumor suppressor and plays critical roles in many aspects of cancer biology, including invasion, metastasis, and angiogenesis (Piletic & Kunej, ). Dysregulated expression of miR‐34c is observed in some carcinomas, such as colorectal cancer (Gu, Wang, Liu, & Xiong, ), breast cancer (Liu et al, ), or even lung cancer (Kim et al, ). We have reported that miR‐34c was upregulated significantly during the progression of AD in the senescence‐accelerated mouse (SAMP8) model by miRNA microarray analysis (Zhou et al, ).…”

Identification of Novel microRNA Prognostic Markers Using Cascaded Wx, a Neural Network-Based Framework, in Lung Adenocarcinoma Patients

“…Spheroid invasion assays were performed as described previously [ 44 ]. Briefly, to create spheroids, lung cancer cells (1 × 10 5 cells/5 mL) in 20% METHOCEL (Sigma-Aldrich) and 1% Matrigel (BD Biosciences, Franklin Lakes, NJ, USA) were hung on the lid of 15 cm dishes (50 μL/drop) and incubated at 37 °C for 2 days.…”

Non-Coding RNAs in Lung Tumor Initiation and Progression

“…Spheroid cultures serve as 3-D models that can demonstrate cell aggregation and tumor progression. Kim et al looked at the role of miR-34 on cancer cell invasion by using spheroid cultures and found that miR-34b/c significantly suppressed spheroid invasion and EMT [297]. Ekert and colleagues compared 3-D spheroid cultures with 2-D monolayer cultures for multiple EGFR wild type and mutated cell lines and found that 3-D spheroids were able to reproduce proliferative processes.…”