Abstract
Colorectal cancer (CRC) is characterized by genetic heterogeneity and is often diagnosed at an advanced stage. Therefore, there is a need to identify novel predictive markers. Yin Yang 1 (YY1) is a transcription factor playing a dual role in cancer. The present study aimed to investigate whether YY1 expression levels influence CRC cell response to therapy and to identify the transcriptional targets involved. The diagnostic and prognostic values of YY1 and the identified factor(s) in CRC patients were also explored. Silencing of YY1 increased the resistance to 5-Fluorouracil-induced cytotoxicity in two out of four CRC cells with different genotypes. BCL2L15/Bfk pro-apoptotic factor was found selectively expressed in the responder CRC cells and downregulated upon YY1 knockdown. CRC dataset analyses corroborated a tumor-suppressive role for both YY1 and BCL2L15 whose expressions were inversely correlated with aggressiveness. CRC single-cell sequencing dataset analyses demonstrated higher co-expression levels of both YY1 and BCL2L15 within defined tumor cell clusters. Finally, elevated levels of YY1 and BCL2L15 in CRC patients were associated with larger relapse-free survival. Given their observed anti-cancer role, we propose YY1 and BCL2L15 as candidate diagnostic and prognostic CRC biomarkers.
Highlights
IntroductionGiven the high intrinsic genomic instability, Colorectal Cancer (CRC) shows an elevated inter-patient and intra-tumor heterogeneity, both associated with poorer outcomes [3]
Colorectal Cancer (CRC) represents about 10% of the overall diagnosed tumors [1]. within the last ten years the survival rate has increased thanks to an augmented adhesion to screening and preventive measures, the mortality still remains significant [2].Given the high intrinsic genomic instability, CRC shows an elevated inter-patient and intra-tumor heterogeneity, both associated with poorer outcomes [3]
Four human CRC cell lines, HT-29, SW620, HCT-116 and Caco-2, each with a different mutational background, were selected for the study in an effort to delineate the correlation between the genetic background and the expression of Yin Yang 1 (YY1) (Supplementary Table S1)
Summary
Given the high intrinsic genomic instability, CRC shows an elevated inter-patient and intra-tumor heterogeneity, both associated with poorer outcomes [3]. A constant refinement of the CMS classification through the discovery of novel molecular features may lead to an increase in their predictive impact [5]. These molecular features largely influence tumor aggressiveness, metastasis formation, development of drug resistance, as well as relapses over the years [6]. It is important to characterize the molecular mechanisms orchestrating CRC pathogenesis, which, in turn, will allow the improvement of diagnostic, prognostic and therapeutic strategies in this era of personalized medicine [7]
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