FAM64A: A Novel Oncogenic Target of Lung Adenocarcinoma Regulated by Both Strands of miR-99a (miR-99a-5p and miR-99a-3p).

Keiko Mizuno,Kengo Tanigawa,Naohiko Seki,Shunsuke Misono,Shogo Moriya,Takayuki Suetsugu,Reona Okada,Nijiro Nohata,Hiromasa Inoue,Shunichi Asai

doi:10.3390/cells9092083

Keiko Mizuno, Kengo Tanigawa + Show 8 more

Open Access

https://doi.org/10.3390/cells9092083

Copy DOI

Journal: Cells	Publication Date: Sep 11, 2020
Citations: 17	License type: CC BY 4.0

Affiliation: Kagoshima University, Chiba University, MSD (Japan)

Abstract

Lung adenocarcinoma (LUAD) is the most aggressive cancer and the prognosis of these patients is unfavorable. We revealed that the expression levels of both strands of miR-99a (miR-99a-5p and miR-99a-3p) were significantly suppressed in several cancer tissues. Analyses of large The Cancer Genome Atlas (TCGA) datasets showed that reduced miR-99a-5p or miR-99a-3p expression is associated with worse prognoses in LUAD patients (disease-free survival (DFS): p = 0.1264 and 0.0316; overall survival (OS): p = 0.0176 and 0.0756, respectively). Ectopic expression of these miRNAs attenuated LUAD cell proliferation, suggesting their tumor-suppressive roles. Our in silico analysis revealed 23 putative target genes of pre-miR-99a in LUAD cells. Among these targets, high expressions of 19 genes were associated with worse prognoses in LUAD patients (OS: p < 0.05). Notably, FAM64A was regulated by both miR-99a-5p and miR-99a-3p in LUAD cells, and its aberrant expression was significantly associated with poor prognosis in LUAD patients (OS: p = 0.0175; DFS: p = 0.0276). FAM64A knockdown using siRNAs suggested that elevated FAM64A expression contributes to cancer progression. Aberrant FAM64A expression was detected in LUAD tissues by immunostaining. Taken together, our miRNA-based analysis might be effective for identifying prognostic and therapeutic molecules in LUAD.

Highlights

Lung cancer is one of the most common and lethal cancers
There is a population of Lung adenocarcinoma (LUAD) patients who harbor no driver gene mutations, indicating that several distinct molecular and genetic pathways contribute to LUAD progression
The miRNA-seq data showed that expression levels of miR-99a-5p and miR-99a-3p were significantly suppressed in LUAD tissues compared with normal lung tissues (Figure 1A)

Summary

Introduction

Lung cancer is one of the most common and lethal cancers. In 2018, approximately 2.1 million people were diagnosed with this disease, and 1.8 million patients died from it [1]. NSCLC includes squamous cell carcinoma, adenocarcinoma and large-cell carcinoma [2]. Among NSCLCs, lung adenocarcinoma (LUAD) is the most common, and it is often at an advanced. Cells 2020, 9, 2083 stage by the time of diagnosis, and the prognosis of the patients is unfavorable (5-year survival rate on average below 20% on average) [3]. The survival rate of LUAD patients has improved because of the development of molecularly targeted drugs and immune checkpoint inhibitors [4,5,6]. Various molecular targeted agents have become available, based on driver gene mutations in LUAD [5,6,7]. There is a population of LUAD patients who harbor no driver gene mutations, indicating that several distinct molecular and genetic pathways contribute to LUAD progression

Methods

Results

Discussion

Conclusion