MRNAsi Index: Machine Learning in Mining Lung Adenocarcinoma Stem Cell Biomarkers.

Yitong Zhang,Joseph Ta-Chien Tseng,Hui Li,I-Chia Lien,Wei Wu,Fenglan Li

doi:10.3390/genes11030257

Yitong Zhang, Joseph Ta-Chien Tseng + Show 4 more

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https://doi.org/10.3390/genes11030257

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Abstract

Cancer stem cells (CSCs), characterized by self-renewal and unlimited proliferation, lead to therapeutic resistance in lung cancer. In this study, we aimed to investigate the expressions of stem cell-related genes in lung adenocarcinoma (LUAD). The stemness index based on mRNA expression (mRNAsi) was utilized to analyze LUAD cases in the Cancer Genome Atlas (TCGA). First, mRNAsi was analyzed with differential expressions, survival analysis, clinical stages, and gender in LUADs. Then, the weighted gene co-expression network analysis was performed to discover modules of stemness and key genes. The interplay among the key genes was explored at the transcription and protein levels. The enrichment analysis was performed to annotate the function and pathways of the key genes. The expression levels of key genes were validated in a pan-cancer scale. The pathological stage associated gene expression level and survival probability were also validated. The Gene Expression Omnibus (GEO) database was additionally used for validation. The mRNAsi was significantly upregulated in cancer cases. In general, the mRNAsi score increases according to clinical stages and differs in gender significantly. Lower mRNAsi groups had a better overall survival in major LUADs, within five years. The distinguished modules and key genes were selected according to the correlations to the mRNAsi. Thirteen key genes (CCNB1, BUB1, BUB1B, CDC20, PLK1, TTK, CDC45, ESPL1, CCNA2, MCM6, ORC1, MCM2, and CHEK1) were enriched from the cell cycle Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, relating to cell proliferation Gene Ontology (GO) terms, as well. Eight of the thirteen genes have been reported to be associated with the CSC characteristics. However, all of them have been previously ignored in LUADs. Their expression increased according to the pathological stages of LUAD, and these genes were clearly upregulated in pan-cancers. In the GEO database, only the tumor necrosis factor receptor associated factor-interacting protein (TRAIP) from the blue module was matched with the stemness microarray data. These key genes were found to have strong correlations as a whole, and could be used as therapeutic targets in the treatment of LUAD, by inhibiting the stemness features.

Highlights

Lung cancer is the leading fatal malignancy worldwide, causing over 1.5 million cancer-related deaths annually [1,2]; and it is classified into two main subtypes: non-small cell lung cancer (NSCLC, making up 80–85% of all lung cancers) and small-cell lung cancer (SCLC, making up 15–20% of cases) [3,4]
According to the clinical stage of the cases, we found that the early-stage lung cancer mRNA expression (mRNAsi) score was lower than the middle and advanced stage lung adenocarcinoma (LUAD) group (Figure 3d), there was a small decrease in the stage III lung cancer group (p-value = 0.015, < 0.05)
In our previous research on drug resistance of lung adenocarcinoma, we have found that microtubules can be a target for sulforaphane (SFN) to reduce the drug resistance of paclitaxel (PTX), which agrees well with the above analysis [29]

Summary

Introduction

Lung cancer is the leading fatal malignancy worldwide, causing over 1.5 million cancer-related deaths annually [1,2]; and it is classified into two main subtypes: non-small cell lung cancer (NSCLC, making up 80–85% of all lung cancers) and small-cell lung cancer (SCLC, making up 15–20% of cases) [3,4]. The widely accepted hypothesis of CSCs, in the field of oncology, suggests that the heterogeneity within a solid tumor follows a hierarchical cell dynamic and the emergence of a small subpopulation of normal somatic stem cells [11] In this way, the CSC subpopulation is consistently maintained, preserving its characteristics of self-perpetuation and generation of differentiated progeny through asymmetrical division, which gives rise to heterogenic tumors. The CSC population has been shown to expand during periods of stress, including chemotherapy treatments, such as cisplatin and 5’fluorouracil, through a symmetrically dividing way. This process makes therapies ineffective for certain kinds of cancers [12]

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