Ananya Luthria

Background: Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality worldwide, with death occurring primarily due to metastasis, recurrence, and resistance to therapy¹. Current treatment strategies, including surgery and chemotherapy, often provide limited long-term success because they fail to effectively target the molecular mechanisms driving tumor progression and cancer stem cell (CSC) survival². Increasing evidence has shown that colorectal CSCs contribute significantly to tumor initiation, metastasis, recurrence, and chemoresistance³. Recent research has focused on microRNAs (miRNAs), small noncoding RNAs that regulate gene expression and influence pathways involved in proliferation, apoptosis, stemness, invasion, immune evasion, and angiogenesis⁴. Prior studies have identified both tumor-suppressive and oncogenic miRNAs involved in CRC progression; however, gaps remain in understanding how these miRNAs mechanistically regulate CSC behavior and how they may serve as therapeutic targets or prognostic biomarkers. This literature review examines the mechanistic roles of miRNAs in colorectal CSCs and evaluates their potential clinical relevance in improving CRC treatment outcomes.

Objective(s): The purpose of this literature review was to evaluate the mechanistic roles of microRNAs in colorectal cancer stem cells and determine their significance as therapeutic targets and prognostic biomarkers in colorectal cancer. Specifically, this review focused on how dysregulated miRNAs regulate pathways associated with proliferation, stemness, chemoresistance, immune evasion, and metastasis.

Search Methods: A literature search was conducted using PubMed and Google Scholar databases for articles published between 2017 and 2023. Search strategies included MeSH terms and keywords such as “colorectal cancer,” “cancer stem cells,” “microRNA,” “miRNA,” “chemoresistance,” “Notch signaling,” “miR-195-5p,” “miR-664b-3p,” “PD-L1,” and “exosomal microRNAs.” Primary research studies investigating the mechanistic and functional roles of miRNAs in CRC stem cells were selected for review.

Results: The reviewed studies demonstrated that multiple miRNAs regulate key pathways involved in colorectal cancer progression and CSC maintenance. Tumor-suppressive miRNAs, including miR-664b-3p and miR-195-5p, were found to inhibit proliferation, migration, stemness, and chemoresistance. miR-664b-3p suppressed CRC progression through direct inhibition of BUB3, leading to decreased proliferation and increased apoptosis⁵. miR-195-5p targeted Notch2 and RBPJ, suppressing Notch signaling and reducing CSC self-renewal, tumor sphere formation, and resistance to 5-fluorouracil chemotherapy. In contrast, oncogenic miRNAs such as miR-17-5p promoted tumor progression and immune evasion through exosome-mediated suppression of SPOP and increased PD-L1 expression, resulting in decreased T-cell activity and enhanced tumor growth⁶. Collectively, these studies showed that miRNAs regulate multiple oncogenic pathways involved in proliferation, stemness, immune escape, and metastasis in colorectal cancer stem cells.

Conclusion: MicroRNAs are critical mechanistic regulators of colorectal cancer stem cell survival and tumor progression. By simultaneously regulating pathways associated with proliferation, chemoresistance, stemness, angiogenesis, and immune evasion, miRNAs represent promising therapeutic targets and prognostic biomarkers for colorectal cancer. The findings from this review suggest that targeting dysregulated miRNA networks may improve treatment responsiveness and long-term clinical outcomes in CRC patients. Future research should focus on translating miRNA-based therapies into clinical applications, evaluating delivery methods and safety profiles, and further investigating the role of miRNAs in treatment resistance and tumor recurrence.

Works Cited:

1. Shin AE, Giancotti FG, Rustgi AK. Metastatic colorectal cancer: mechanisms and emerging therapeutics. Trends Pharmacol Sci. 2023;44(4):222-236. doi:10.1016/j.tips.2023.01.003
2. Zhou H, Liu Z, Wang Y, et al. Colorectal liver metastasis: molecular mechanism and interventional therapy. Signal Transduct Target Ther. 2022;7(1):70. Published 2022 Mar 4. doi:10.1038/s41392-022-00922-2
3. Fan CW, Lu R, Fang C, et al. Expression profile, molecular functions, and prognostic significance of miRNAs in primary colorectal cancer stem cells. Aging (Albany NY). 2021;13(8):12067-12085. doi:10.18632/aging.202914
4. Wang H. MicroRNAs and Apoptosis in Colorectal Cancer. Int J Mol Sci. 2020;21(15):5353. Published 2020 Jul 28. doi:10.3390/ijms21155353
5. Zhao LY, Xin GJ, Tang YY, Li XF, Li YZ, Tang N, Ma YH. miR-664b-3p inhibits colon cell carcinoma via negatively regulating Budding uninhibited by benzimidazole 3. Bioengineered. 2022 Mar;13(3):4857-4868. doi: 10.1080/21655979.2022.2036400.
6. Sun W, Cui J, Ge Y, Wang J, Yu Y, Han B, Liu B. Tumor stem cell-derived exosomal microRNA-17-5p inhibits anti-tumor immunity in colorectal cancer via targeting SPOP and overexpressing PD-L1. Cell Death Discov. 2022 Apr 23;8(1):223. doi: 10.1038/s41420-022-00919-4.