Cervical Cancer Stem-Like Cell Transcriptome Profiles Predict Response to Chemoradiotherapy

Abstract

Cervical cancer (CC) represents a major global health issue, particularly impacting women from resource constrained regions worldwide. Treatment refractoriness to standard chemoradiotheraphy has identified cancer stem cells as critical coordinators behind the biological mechanisms of resistance, contributing to CC recurrence. In this work, we evaluated differential gene expression in cervical cancer stem-like cells (CCSC) as biomarkers related to intrinsic chemoradioresistance in CC. A total of 31 patients with locally advanced CC and referred to Mário Penna Institute (Belo Horizonte, Brazil) from August 2017 to May 2018 were recruited for the study. Fluorescence-activated cell sorting was used to enrich CD34+/CD45- CCSC from tumor biopsies. Transcriptome was performed using ultra-low input RNA sequencing and differentially expressed genes (DEGs) using Log2 fold differences and adjusted p-value < 0.05 were determined. The analysis returned 1050 DEGs when comparing the Non-Responder (NR) (n=10) and Responder (R) (n=21) groups to chemoradiotherapy. These included a wide-ranging pattern of underexpressed coding genes in the NR vs. R patients and a panel of lncRNAs and miRNAs with implications for CC tumorigenesis. A panel of biomarkers was selected using the rank-based AUC (Area Under the ROC Curve) and pAUC (partial AUC) measurements for diagnostic sensitivity and specificity. Genes overlapping between the 21 highest AUC and pAUC loci revealed seven genes with a strong capacity for identifying NR vs. R patients (ILF2, RBM22P2, ACO16722.1, AL360175.1 and AC092354.1), of which four also returned significant survival Hazard Ratios. This study identifies DEG signatures that provide potential biomarkers in CC prognosis and treatment outcome, as well as identifies potential alternative targets for cancer therapy.

Promising predictive molecular biomarkers for cervical cancer (Review)

“…It has been proposed that the heterogeneous composition of malignant tumors is a characteristic associated with the plasticity and aggressiveness of CCSC, which increase the risk of TR. In this regard, Zuccherato et al ( 143 ) analyzed the transcriptome of a stem cell-enriched population from CC samples from cases of responders and non-responders (NR) to chemoradiotherapy. Notably, among diverse genes and ncRNAs, they found four miRNAs that were overexpressed in NR (miR-4278, miR-4422, miR-4779 and miR-1268B), with 16 putative targets with a significant negative correlation identified by binding prediction.…”

Unveiling diagnostic and therapeutic strategies for cervical cancer: biomarker discovery through proteomics approaches and exploring the role of cervical cancer stem cells

“…It is believed that CSCs are crucial in the growth and expansion of malignant tumors, as they may be responsible for tumor initiation, growth, and metastasis. They make up only a small fraction of tumor cells, ranging from 0.1% to 10%, and express lower levels of tumor-associated antigens compared to other tumor cells ( 88 ). Following cytotoxic treatments, there is an enrichment of cancer stem cells in residual tumor cells, suggesting their role in chemoresistance and disease relapse.…”

Emerging Roles and Potential Applications of Non-Coding RNAs in Cervical Cancer

“…Despite HPV infection being the most common cause of CC, CSCs also play an important role in the disease’s development, metastasis, recurrence, and prognosis [ 169 ]. CSCs play a significant role in the recurrence and metastasis of patients with cervical carcinoma [ 170 , 171 ].…”