Gene Expression Profiles Associated with Radio-Responsiveness in Locally Advanced Rectal Cancer

Abstract

LARC patients were sorted according to their radio-responsiveness and patient-derived organoids were established from the respective cancer tissues. Expression profiles for each group were obtained using RNA-seq. Biological and bioinformatic analysis approaches were used in deciphering genes and pathways that participate in the radio-resistance of LARC. Thirty candidate genes encoding proteins involved in radio-responsiveness–related pathways, including the immune system, DNA repair and cell-cycle control, were identified. Interestingly, one of the candidate genes, cathepsin E (CTSE), exhibited differential methylation at the promoter region that was inversely correlated with the radio-resistance of patient-derived organoids, suggesting that methylation status could contribute to radio-responsiveness. On the basis of these results, we plan to pursue development of a gene chip for diagnosing the radio-responsiveness of LARC patients, with the hope that our efforts will ultimately improve the prognosis of LARC patients.

Patient-derived rectal cancer organoids—applications in basic and translational cancer research

“…receptor catabolic processes (NPC1, APOE, LGMN), and plasma membrane proteolysis (ADAM9, BACE1, CTSE). They found the enhanced expression of CTSE regulated by DNA methylation status in RR organoids, suggesting that CTSE could be applied as a biomarker for radio-responsiveness (49).…”

“…In RR organoids, up-regulation genes that encode the control protein include calcium-dependent interactions (ANXA2, S100A4), immune cell activation (CD55, IL18, RUNX3), receptor catabolic processes (NPC1, APOE, LGMN), and plasma membrane proteolysis (ADAM9, BACE1, CTSE). They found the enhanced expression of CTSE regulated by DNA methylation status in RR organoids, suggesting that CTSE could be applied as a biomarker for radio-responsiveness ( 49 ).…”

Biological Mechanisms to Reduce Radioresistance and Increase the Efficacy of Radiotherapy: State of the Art

“…Methylation profiles of HNSCC patients identified an RT-related methylation signature in four genes ( ZNF10 , TMPRSS12 , ERGIC2 , RNF215 ), which was able to predict survival outcomes [ 64 ]. The methylation status of cathepsin E ( CTSE ) was inversely correlated with the radioresistance of patient-derived organoids [ 65 ]. The overexpression of DNA methyltransferase 3B (DNMT3B) following IR has been reported to be responsible for the radioresistance of nasopharyngeal carcinoma cells by suppressing the p53-mediated apoptotic pathway [ 66 ].…”

“…Many data are available for established radioresistant cell lines cultured in laboratories, but few recent studies have performed genome-wide analyses on tumor tissues (or organoids) derived from patients. In the study of Lee et al [ 65 ], an organoid model of rectal cancer cells derived from patients was used to identify differentially expressed genes associated with radio-responsiveness. The authors were able to identify enriched pathways associated with radioresistance, which included DNA repair, immune response, and cell cycle progression pathways.…”

“…However, many studies on tumor radioresistance have reported changes in the expression of microRNAs (miRNAs), which are small, well-known ncRNAs that modulate the expression of many genes belonging to different pathways [ 86 ]. Thanks to genome-wide analyses carried out by microarray and RNA sequencing technologies, it is possible to identify differentially expressed miRNA species in radioresistant lung [ 87 ], breast [ 88 , 89 ], nasopharyngeal [ 90 ], prostate [ 91 ], rectal [ 65 ], head and neck, and cervical tumors [ 89 ].…”