Sequenciamento de nova geração revela que a regulação positiva de PNMA3 e RASSF2 está associada à resistência quimioradioterápica em pacientes com câncer de colo uterino

Abstract

Cervical cancer (CC) affects women in global scale and many factors are responsible for the high mortality rate related to this cancer, such as chemoradiotherapy resistance including the cisplatin resistance (CPR) and late diagnosis. Between the hallmarks of cancer is the inhibition of apoptotic pathways, a modulation weakly knows considering both the chemoradiotherapy resistance and CC. Thus, the objective of this study was to identify differentially expressed genes (DEGs) related to apoptosis between Responder (R) and Non-responder (NR) patients to the chemoradiotherapy, as well as the number of immune cells in the tumor microenvironment (TME). For this purpose, 21 R and 10 NR women were included in this study and your cervical cancer non-stem-like cells (CCNSCs) were selected in Fluorescence-activated cell sorting (FACS). Then, the RNA-Seq was performed and all sequences were evaluated according to quality, and those with Phread < 25 as well as adapters were trimmed. The sequences pass-filter were uniquely mapped to the specific Homo sapiens genome loci and the read counts were submitted to the differential expression analysis comparing R to NR patients. Finally, the selection of the biomarkers was achieved in gene ontology (GO), statistical and decision tree analyses, as well as the nº of tumor-infiltrating lymphocytes (TILs) and tumor associated tissue eosinophilia (TATES) were evaluated in morphometric analysis. In morphometric analysis, 23 patients were included according to inclusion criteria. Altogether, 2519 DEGs with log2FC > 1 or < -1 and pajd value < 0.05 were found, 117 of them were linked to apoptosis and only 8 were relevant according to statistical and decision tree analyses. Between the relevant DEGs, the PNMA3 and RASSF2 were upregulated in NR patients and downregulated in R considering all analyses performed. Furthermore, a high number of intratumoral TILs and TATES occurred in the R group, while the NR had a high number of stromal TILs. Therefore, the genes PNMA3 and RASSF2 upregulated in NR patients were considered as potential biomarkers related to apoptosis and chemoradiotherapy resistance, as well as a larger nº of intratumoral TILs and TATES were associated to the positive chemoradiotherapy responses in CC. Nonetheless, more studies still need to be done to confirm the likely interactions among PNMA3, RASSF2, apoptosis and chemoradiotherapy resistance in the CC.