Investigator
Instituto Nacional De Cancerologa
HOTAIR Promotes the Hyperactivation of PI3K/Akt and Wnt/β-Catenin Signaling Pathways via PTEN Hypermethylation in Cervical Cancer
The mechanisms underlying the sustained activation of the PI3K/AKT and Wnt/β-catenin pathways mediated by HOTAIR in cervical cancer (CC) have not been extensively described. To address this knowledge gap in the literature, we explored the interactions between these pathways by driving HOTAIR expression levels in HeLa cells. Our findings reveal that HOTAIR is a key regulator in sustaining the activation of both signaling pathways. Specifically, altering HOTAIR expression—either by knockdown or overexpression—significantly influenced the transcriptional activity of the PI3K/AKT and Wnt/β-catenin pathways. Additionally, we discovered that HIF1α directly induces HOTAIR transcription, which in turn leads to the epigenetic silencing of the PTEN promoter via DNMT1. This process leads to the sustained activation of both pathways, highlighting a novel regulatory axis involving HOTAIR and HIF1α in cervical cancer. Our results suggest a new model in which HOTAIR sustains reciprocal activation of the PI3K/AKT and Wnt/β-catenin pathways through the HOTAIR/HIF1α axis, thereby contributing to the oncogenic phenotype of cervical cancer.
A microRNA Profile Regulates Inflammation-Related Signaling Pathways in Young Women with Locally Advanced Cervical Cancer
Cervical cancer (CC) remains among the most frequent cancers worldwide despite advances in screening and the development of vaccines against human papillomavirus (HPV), involved in virtually all cases of CC. In mid-income countries, a substantial proportion of the cases are diagnosed in advanced stages, and around 40% of them are diagnosed in women under 49 years, just below the global median age. This suggests that members of this age group share common risk factors, such as chronic inflammation. In this work, we studied samples from 46 patients below 45 years old, searching for a miRNA profile regulating cancer pathways. We found 615 differentially expressed miRNAs between tumor samples and healthy tissues. Through bioinformatic analysis, we found that several of them targeted elements of the JAK/STAT pathway and other inflammation-related pathways. We validated the interactions of miR-30a and miR-34c with JAK1 and STAT3, respectively, through dual-luciferase and expression assays in cervical carcinoma-derived cell lines. Finally, through knockdown experiments, we observed that these miRNAs decreased viability and promoted proliferation in HeLa cells. This work contributes to understanding the mechanisms through which HPV regulates inflammation, in addition to its canonical oncogenic function, and brings attention to the JAK/STAT signaling pathway as a possible diagnostic marker for CC patients younger than 45 years. To our knowledge to date, there has been no previous description of a panel of miRNAs or even ncRNAs in young women with locally advanced cervical cancer.
Molecular Differences between Squamous Cell Carcinoma and Adenocarcinoma Cervical Cancer Subtypes: Potential Prognostic Biomarkers
The most frequently diagnosed histological types of cervical cancer (CC) are squamous cell carcinoma (SCC) and adenocarcinoma (ADC). Clinically, the prognosis of both types is controversial. A molecular profile that distinguishes each histological subtype and predicts the prognosis would be of great benefit to CC patients. Methods: The transcriptome of CC patients from The Cancer Genome Atlas (TCGA) was analyzed using the DESeq2 package to obtain the differentially expressed genes (DEGs) between ADC and SCC. The DEGs were validated on a publicly available Mexican-Mestizo patient transcriptome dataset (GSE56303). The global biological pathways involving the DEGs were obtained using the Webgestalt platform. The associations of the DEGs with Overall Survival (OS) were assessed. Finally, three DEGs were validated by RT-qPCR in an independent cohort of Mexican patients. Results. The molecular profiles of ADC and SCC of the CC patients of the TCGA database and the Mexican-Mestizo cohort (GSE56303) were determined obtaining 1768 and 88 DEGs, respectively. Strikingly, 70 genes were concordant—with similar Log2FoldChange values—in both cohorts. The 70 DEGs were involved in IL-17, JAK/STAT, and Ras signaling. Kaplan-Meier OS analysis from the Mexican-Mestizo cohort showed that higher GABRB2 and TSPAN8 and lower TMEM40 expression were associated with better OS. Similar results were found in an independent Mexican cohort. Conclusions: Molecular differences were detected between the ADC and SCC subtypes; however, further studies are required to define the appropriate prognostic biomarker for each histological type.
