Colorectal cancer (CRC) remains the second most lethal cancer worldwide, with incidence rates expected to rise substantially by 2040. Although biomarker-driven therapies have improved treatment, responses to standard chemotherapeutics, such as 5-fluorouracil (5-FU), oxaliplatin, and irinotecan, vary considerably. This clinical heterogeneity emphasizes the urgent need for novel biomarkers that can guide therapeutic decisions and overcome chemoresistance. microRNAs (miRNAs) have emerged as key post-transcriptional regulators that critically influence chemotherapy responses. miRNAs orchestrate post-transcriptional gene regulation and modulate diverse pathways linked to chemoresistance. They influence drug transport by regulating ABC transporters and affect metabolic enzymes like thymidylate synthase (TYMS). These activities shape responses to standard CRC chemotherapy agents. Furthermore, miRNAs can regulate the epithelial–mesenchymal transition (EMT). The miR-200 family (e.g., miR-200c and miR-141) can reverse EMT phenotypes, restoring chemosensitivity. Additionally, miRNAs like miR-19a and miR-625-3p show predictive value for chemotherapy outcomes. Despite these promising findings, the clinical translation of miRNA-based biomarkers faces challenges, including methodological inconsistencies and the dynamic nature of miRNA expression, influenced by the tumor microenvironment. This review highlights the critical role of miRNAs in elucidating chemoresistance mechanisms and their promise as biomarkers and therapeutic targets in CRC, paving the way for a new era of precision oncology.

Colorectal cancer (CRC) is the second leading cause of cancer deaths globally. While ethnic differences in driver gene mutations have been documented, the South American population remains understudied at the genomic level, despite facing a rising burden of CRC. We analyzed tumors of 40 Chilean CRC patients (Chp) using next-generation sequencing and compared them to data from mainly Caucasian cohorts (TCGA and MSK-IMPACT). We identified 388 mutations in 96 out of 135 genes, with TP53 (45%), KRAS (30%), PIK3CA (22.5%), ATM (20%), and POLE (20%) being the most frequently mutated. TSC2 mutations were associated with right colon cancer (44.44% in RCRC vs. 6.45% in LCRC, p-value = 0.016), and overall frequency was higher compared to TCGA (p-value = 1.847 × 10⁻⁵) and MSK-IMPACT cohorts (p-value = 3.062 × 10⁻²). Limited sample size restricts definitive conclusions, but our data suggest potential differences in driver mutations for Chilean patients, being that the RTK-RAS oncogenic pathway is less affected and the PI3K pathway is more altered in Chp compared to TCGA (45% vs. 25.56%, respectively). The prevalence of actionable pathways and driver mutations can guide therapeutic choices, but can also impact treatment effectiveness. Thus, these findings warrant further investigation in larger Chilean cohorts to confirm these initial observations. Understanding population-specific driver mutations can guide the development of precision medicine programs for CRC patients.

Chemoresistance is one of the major barriers to effective treatment in gastric cancer (GC), contributing to disease progression and poor patient survival. SRY-box transcription factor 5 (SOX5) has been associated with aggressive cancer phenotypes in several malignancies; however, its relationship with chemoresistance in GC has yet to be fully characterized. This study investigated whether SOX5 expression is associated with molecular features linked to aggressive GC phenotypes, including multi-drug resistance proteins, cancer stem cell (CSC) antigens, epithelial–mesenchymal transition (EMT) markers, and proteins involved in drug efflux and DNA repair. SOX5 expression was evaluated in AGS and MKN-45 GC cell lines using Western blotting, real-time quantitative PCR, and immunofluorescence. Markers associated with EMT (Snail1, ZEB1, and E-cadherin), CSC phenotypes (CD44 and CD133), DNA repair (XRCC1 and ERCC2), and drug efflux (ABCB1) were analyzed. Cellular sensitivity to 5-fluorouracil (5-FU) and oxaliplatin (Ox) was assessed using an MTT-based viability assay. In addition, publicly available GC datasets were analyzed to evaluate the association between SOX5 expression and overall survival. AGS cells exhibited significantly higher SOX5 expression at both the mRNA and protein levels compared with MKN-45 cells. High SOX5 expression was associated with increased expression of the transcription factors Snail1 and ZEB1, which are associated with EMT, leading to decreased E-cadherin expression. Furthermore, SOX5 expression was associated with increased expression of CD133, the DNA repair genes XRCC1 and ERCC2, and ABCB1 transcripts. Consistent with these molecular findings, AGS cells exhibited greater viability following exposure to 5-FU and Ox, either alone or in combination, suggesting reduced sensitivity to these agents. Furthermore, high SOX5 expression was associated with poorer overall survival across independent GC patient cohorts. Overall, these findings suggest SOX5 as a potential biomarker associated with an aggressive molecular phenotype characterized by EMT activation, enhanced DNA repair capacity, stemness-associated features, and reduced sensitivity to FOLFOX-based chemotherapy. Future mechanistic studies are warranted to establish whether SOX5 directly drives these processes.