The involvement of LncRNA SOX2‐overlapping transcript (SOX2‐OT), SOX2, and GLI‐1 transcription factors in cancer has been well documented. Nonetheless, it is still unknown whether co‐expressed SOX2‐OT/SOX2 or SOX2‐OT/SOX2/GLI‐1 axes are epigenetically/transcriptionally involved in terms of resistance to oncology therapy and in poorer clinical outcomes for patients with lung cancer. We evaluated the role of SOX2‐OT/SOX2 and SOX2‐OT/SOX2/GLI‐1 axes using RT‐qPCR, western blot, immunofluorescence analyses, gene silencing, cellular cytotoxic, and ChIP‐qPCR assays on human cell lines, solid lung malignant tumors, and normal lung tissue. We detected that the SOX2‐OT/SOX2/GLI‐1 axis promotes resistance to tyrosine kinase inhibitor (TKI)‐erlotinib and cisplatin‐based therapy. Evidence from this study show that SOX2‐OT modulates the expression/activation of EGFR‐pathway members AKT/ERK. Further, both SOX2‐OT and GLI‐1 genes are epigenetically regulated at their promoter sequences, in an LncRNA SOX2‐OT‐dependent manner, mainly through modifying the enrichment of the activation histone mark H3K4me3/H3K27Ac, versus the repressive histone mark H3K9me3/H3K27me3. In addition, we identified that inhibition of SOX2‐OT and reduced expression of SOX2/GLI‐1 sensitizes lung cancer cells to EGFR/TKI‐erlotinib or cisplatin‐based treatment. Finally, we show that high co‐expression of SOX2‐OT/SOX2 transcripts and SOX2/GLI‐1 proteins appears to correlate with a poor clinical prognosis and lung malignant phenotype. Collectively, these results present evidence that LncRNA SOX2‐OT modulates an orchestrated resistance mechanism, promoting poor prognosis and human lung malignancy through genetic, epigenetic, and post‐translational mechanisms.

Respiratory diseases hold several genome, epigenome, and transcriptional aberrations as a cause of the accumulated damage promoted by, among others, environmental risk factors. Such aberrations can also come about as an adaptive response when faced with therapeutic oncological drugs. In epigenetic terms, aberrations in DNA methylation patterns, histone code marks balance, and/or chromatin-remodeling complexes recruitment, among Polycomb Repressive Complex-2 (PRC2) versus Trithorax (TRX) Activator Complex, have been proposed to be affected by several previously characterized functional long non-coding RNAs (lncRNAs). Such molecules are involved in modulating and/or controlling lung cancer epigenome and genome expression, as well as in malignancy and clinical progression in lung cancer. Several recent reports have described diverse epigenetic modifications in lung cancer cells and solid tumors, among others genomic DNA methylation and post-translational modifications (PTMs) on histone tails, as well as lncRNAs patterns and levels of expression. However, few systematic approaches have attempted to demonstrate a biological function and clinical association, aiming to improve therapeutic decisions in basic research and lung clinical oncology. A widely used example is the lncRNA HOTAIR and its functional histone mark H3K27me3, which is directly associated to the PRC2; however, few systematic pieces of solid evidence have been experimentally performed, conducted and/or validated to predict lung oncological therapeutic efficacy. Recent evidence suggests that chromatin-remodeling complexes accompanied by lncRNAs profiles are involved in several comprehensive lung carcinoma clinical parameters, including histopathology progression, prognosis, and/or responsiveness to unique or combined oncological therapies. The present manuscript offers a systematic revision of the current knowledge about the major epigenetic aberrations represented by changes in histone PTMs and lncRNAs expression levels and patterns in human lung carcinomas in cancer drug-based treatments, as an important comprehensive knowledge focusing on better oncological therapies. In addition, a new future direction must be refocusing on several gene target therapies, mainly on pharmaceutical EGFR-TKIs compounds, widely applied in lung cancer, currently the leading cause of death by malignant diseases.

Malignant pleural mesothelioma (MPM) is a rare but aggressive tumor that originates in the pleura, is diagnosed in advanced stages and has a poor prognosis. Accurate diagnosis of MPM is often difficult and complex, and the gold standard diagnosis test is based on qualitative analysis of markers in pleural tissue by immunohistochemical staining. Therefore, it is necessary to develop quantitative and non-subjective alternative diagnostic tools. MicroRNAs are non-coding RNAs that regulate essential cellular mechanisms at the post-transcriptional level. Recent evidence indicates that miRNA expression in tissue and body fluids is aberrant in various tumors, revealing miRNAs as promising diagnostic biomarkers. This review summarizes evidence regarding secreted and tissue miRNAs as biomarkers of MPM and the biological characteristics associated with their potential diagnostic value. In addition to studies regarding miRNAs with potential diagnostic value for MPM, studies that aimed to identify the miRNAs involved in molecular mechanisms associated with MPM development are described with an emphasis on relevant aspects of the experimental designs that may influence the accuracy, consistency and real diagnostic value of currently reported data.