Dysregulation of Transcription Factor Networks Unveils Different Pathways in Human Papillomavirus 16-Positive Squamous Cell Carcinoma and Adenocarcinoma of the Uterine Cervix

Abstract

Squamous cell carcinoma (SCC) and adenocarcinoma (ADC) are the most common histological types of cervical cancer (CC). The worse prognosis of ADC cases highlights the need for better molecular characterization regarding differences between these CC types. RNA-Seq analysis of seven SCC and three ADC human papillomavirus 16-positive samples and the comparison with public data from non-tumoral human papillomavirus-negative cervical tissue samples revealed pathways exclusive to each histological type, such as the epithelial maintenance in SCC and the maturity-onset diabetes of the young (MODY) pathway in ADC. The transcriptional regulatory network analysis of cervical SCC samples unveiled a set of six transcription factor (TF) genes with the potential to positively regulate long non-coding RNA genes DSG1-AS1, CALML3-AS1, IGFL2-AS1, and TINCR. Additional analysis revealed a set of MODY TFs regulated in the sequence predicted to be repressed by miR-96-5p or miR-28-3p in ADC. These microRNAs were previously described to target LINC02381, which was predicted to be positively regulated by two MODY TFs upregulated in cervical ADC. Therefore, we hypothesize LINC02381 might act by decreasing the levels of miR-96-5p and miR-28-3p, promoting the MODY activation in cervical ADC. The novel TF networks here described should be explored for the development of more efficient diagnostic tools.

Molecular Differences between Squamous Cell Carcinoma and Adenocarcinoma Cervical Cancer Subtypes: Potential Prognostic Biomarkers

“…Likewise, Chao A. et al, through microarray assays, revealed a profile of DEGs between ADC and SCC samples from CC patients; TSPAN-3, CEACAM5, TACSTD1, MSLN, and S100P were of particular interest, as they were overexpressed in ADC [ 15 ]. Moreover, transcription factors encoding genes PAX6, PDX1, HNF4A, HNF1A, HNF4G, and FOXA3 show higher expression levels in cervical ADC as compared with cervical SCC [ 16 ]. These findings confirm that there are molecular differences between ADC and SCC.…”

“…In another study, using microarrays and RT-qPCR assays, Chao A. et al identified a group of four genes (CEACAM5, TACSTD1, S100P, and MSLN) that were overexpressed in ADC vs. SCC; in this study, CEACAM and TACSTD1 were prognostic factors [ 15 ]. Moreover, transcription factors encoding genes PAX6, PDX1, HNF4A, HNF1A, HNF4G, and FOXA3 show higher expression levels in cervical ADC as compared with cervical SCC [ 16 ]. These findings demonstrate that it is conceivable to describe different gene profiles for ADC and SCC.…”

IGFL2-AS1, a Long Non-Coding RNA, Is Associated with Radioresistance in Colorectal Cancer

“…The relative levels of IGFL2-AS1 transcripts were higher in RR patient samples, suggesting a possible role for IGFL2-AS1 in radioresistance. Interestingly, higher levels of IGFL2-AS1 transcript have been reported in various cancers [ 5 , 6 , 7 , 8 ], and an esophageal cancer-trap project [ 9 ] in cBioPortal [ 10 ] showed that the IGFL2-AS1 gene was amplified in cancer ( Supplementary Figure S1 ). High levels of IGFL2-AS1 transcripts were also associated with poor disease-free survival ( Figure 1 B, Supplementary Figure S2 , and Table 1 ) and advanced cancer stages ( Figure 1 C).…”

“…LncRNAs are a class of non-protein-coding RNAs longer than 200 nucleotides that possess biological functions in transcriptional silencing, transcriptional activation, chromosomal modification, and intranuclear transport [ 4 ]. To date, a handful of studies performed on IGFL2-AS1 have reported higher levels of this transcript in renal cell carcinoma [ 5 ], cervical cancer [ 6 ], oral cancer [ 7 ], and gastric cancer [ 8 ]. IGFL2-AS1 appears to play a role in promoting cancer that involves effects on cell proliferation, migration, and epithelial-mesenchymal transition (EMT).…”

ADORA2A-AS1 Restricts Hepatocellular Carcinoma Progression via Binding HuR and Repressing FSCN1/AKT Axis

“…Among noncoding transcripts, long noncoding RNA (lncRNA) is the most numerous, which has over 200 nucleotides in length (11,12). Accumulating evidence has documented that many lncRNAs were aberrantly expressed in various diseases, particular malignancies (13)(14)(15)(16). Furthermore, many lncRNAs were documented to play critical roles in various pathophysiological processes including cancers (17)(18)(19)(20)(21)(22)(23).…”