Identification of Candidate lncRNA and Pseudogene Biomarkers Associated with Carbon-Nanotube-Induced Malignant Transformation of Lung Cells and Prediction of Potential Preventive Drugs

Abstract

Mounting evidence has linked carbon nanotube (CNT) exposure with malignant transformation of lungs. Long non-coding RNAs (lncRNAs) and pseudogenes are important regulators to mediate the pathogenesis of diseases, representing potential biomarkers for surveillance of lung carcinogenesis in workers exposed to CNTs and possible targets to develop preventive strategies. The aim of this study was to screen crucial lncRNAs and pseudogenes and predict preventive drugs. GSE41178 (small airway epithelial cells exposed to single- or multi-walled CNTs or dispersant control) and GSE56104 (lung epithelial cells exposed to single-walled CNTs or dispersant control) datasets were downloaded from the Gene Expression Omnibus database. Weighted correlation network analysis was performed for these two datasets, and the turquoise module was preserved and associated with CNT-induced malignant phenotypes. In total, 24 lncRNAs and 112 pseudogenes in this module were identified as differentially expressed in CNT-exposed cells compared with controls. Four lncRNAs (MEG3, ARHGAP5-AS1, LINC00174 and PVT1) and five pseudogenes (MT1JP, MT1L, RPL23AP64, ZNF826P and TMEM198B) were predicted to function by competing endogenous RNA (MEG3/RPL23AP64-hsa-miR-942-5p-CPEB2/PHF21A/BAMBI; ZNF826P-hsa-miR-23a-3p-SYNGAP1, TMEM198B-hsa-miR-15b-5p-SYNGAP1/CLU; PVT1-hsa-miR-423-5p-PSME3) or co-expression (MEG3/MT1L/ZNF826P/MT1JP-ATM; ARHGAP5-AS1-TMED10, LINC00174-NEDD4L, ARHGAP5-AS1/PVT1-NIP7; MT1L/MT1JP-SYNGAP1; MT1L/MT1JP-CLU) mechanisms. The expression levels and prognosis of all genes in the above interaction pairs were validated using lung cancer patient samples. The receiver operating characteristic curve analysis showed the combination of four lncRNAs, five pseudogenes or lncRNAs + pseudogenes were all effective for predicting lung cancer (accuracy >0.8). The comparative toxicogenomics database suggested schizandrin A, folic acid, zinc or gamma-linolenic acid may be preventive drugs by reversing the expression levels of lncRNAs or pseudogenes. In conclusion, this study highlights lncRNAs and pseudogenes as candidate diagnostic biomarkers and drug targets for CNT-induced lung cancer.

LncRNA‐associated competing endogenous RNA network analysis uncovered key lncRNAs involved in temozolomide resistance and tumor recurrence of glioblastoma

“…Elevated levels of PANDAR expression are correlated with decreased overall survival rates and a reduced duration of recurrence in hepatocellular carcinoma patients 77 . Similar observations are found in our study, for instance, we discovered a lncRNA LINC000174 acting as ceRNA in TMZ‐resistant GBM patients, which has been identified as a cancer biomarker in other cancer types 51,78,79 . Hence, this lncRNA can possibly be useful as a biomarker and potential therapeutic target for TMZ‐resistant GBM and can be investigated further to look for its possibility for personalized medicine.…”

“…77 Similar observations are found in our study, for instance, we discovered a lncRNA LINC000174 acting as ceRNA in TMZ-resistant GBM patients, which has been identified as a cancer biomarker in other cancer types. 51,78,79 Hence, this lncRNA can possibly be useful as a biomarker and potential therapeutic target for TMZ-resistant GBM and can be investigated further to look for its possibility for personalized medicine. In addition, there are many more lncRNAs, which we are hypothesizing to be potential biomarkers in TMZ-resistant GBM.…”

In Vitro Cell Transformation Assays: A Valuable Approach for Carcinogenic Potentiality Assessment of Nanomaterials

“…Nanoceria CeO 2 -NP exposure gave rise to cell transformation (invasion and tumorsphere induction) in association with the altered battery of miRNA expression [61]. A small set of five miRNAs (miR-23a, miR-25, miR-96, miR-210, and miR-502) were reported as biomarkers for nm-induced transformed cells, which were validated particularly for nms (TiO 2 NP, MWCNT, Co-NP, ZnO-NP, and CeO 2 -NP) [56]. A recent bioinformatics-based study highlights lncRNAs (in particular four lncRNA, namely MEG3, ARHGAP5-AS1, LINC00174, and PVT1) and pseudogenes (specifically five pseudogenes, namely MT1JP, MT1L, RPL23AP64, ZNF826P, and TMEM198B) as candidate diagnostic biomarkers and drug targets for CNT-induced lung cancer [83].…”

Pseudogenes in Cancer: State of the Art

“…In another study, Chang et al utilized ceRNA and gene co-expression networks to identify hub lncRNAs and pseudogenes associated with lung cancer [ 126 ]. Among the hundreds of detected interactions, one particular pair, the negative correlation between PVT1 and miR-423-5p, had been previously reported in thyroid cancer and was experimentally validated using dual-luciferase reporter, RNA immunoprecipitation, and RNA pull-down assays [ 127 ].…”