Cholangiocarcinoma (CCA) is an aggressive form of biliary malignancy with a dismal 5-year postoperative survival rate. The incidence of CCA is increasing globally, accounting for approximately 2% of all cancer-related deaths. As such, there is an urgent need for diagnostic and prognostic biomarkers to aid in early disease detection and help guide treatment.
Recently, a review published in the International Journal of Molecular Sciences set out to summarize the various roles of microRNAs (miRNAs) in CCA pathogenesis. The study, led by researchers from Kagawa University in Takamatsu, Japan, also reviewed the diagnostic role of miRNA biomarkers as they apply to disease detection, in addition to their potential role in novel targeted therapeutics.
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Accounting for approximately 3% of all cancers, CCA includes a diverse group of malignancies involving the biliary tree. Asymptomatic in the early stages, CCA is often diagnosed late, leading to a poor prognosis and high mortality rates. Although surgery remains an effective treatment for primary CCA, late-stage disease is often metastatic and is considerably more challenging to treat. This is reflected in a sobering 5-year postoperative survival rate of only 7%-20%, according to the review.
MicroRNAs are a small, noncoding class of RNAs that repress gene expression through interaction with complementary sequences of target mRNAs. Approximately 30% of human genes are regulated by miRNAs through signaling pathways. One-third of human miRNA is also believed to be organized into clusters containing miRNAs with similar nucleotides, which may suggest a synergistic biological effect.
MicroRNAs: The Problem and the Solution
The Japanese review highlights the integral role of miRNAs in CCA pathogenesis. According to the researchers, mounting research has demonstrated that during CCA development, some miRNAs are incorrectly upregulated into “oncogenic miRNAs.” Upregulated oncogenic miRNAs, such as miR-21, promote cancer cell proliferation and metastasis by interfering with the expression of programmed cell death and tissue inhibitor of metalloproteinase 3 (TIMP3).
Several tumor “suppressor” miRNAs — including miR-34a, miR-122, miR-22, and miR-101 — have been shown to be downregulated in many types of cancer. In particular, underexpression of miR-122, a tumor suppressor which inhibits cell proliferation and metastasis by targeting ALDOA and chloride intracellular channel 1 (CLIC1), has been implicated in CCA disease progression.
Timely identification of CCA has proven to be a diagnostic dilemma. Current diagnostic approaches usually involve a combination of clinical history and exam, radiographic imaging, and histologic findings. Although histology is often considered the “gold standard” for diagnosing CCA, current tumor biomarkers have demonstrated poor sensitivity and specificity for the disease. Unfortunately, early-stage CCA is often asymptomatic, while symptomatic disease often portends a late-stage diagnosis with limited treatment options.
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The search for accurate diagnostic biomarkers to aid in early disease detection has focused on miRNAs as a potential solution. The Japanese review cites several studies that have shown how particular miRNAs have both diagnostic and prognostic value in CCA. Examples include miR-21 and miR-221, which can aid in the diagnosis of CCA associated with hepatolithiasis with a sensitivity and specificity of 77.42% and 97.50%, respectively. Increased expression of serum miR-26a has been correlated with poor survival in CCA (HR=4.226, 95% CI, 1.415-10.321) while serum miR-150-5p expression is downregulated in patients suffering from CCA, demonstrating a 91.43% sensitivity and 80% diagnostic specificity.
For patients with late-stage disease who would not benefit from surgical resection, traditional chemotherapeutics such as gemcitabine and cisplatin (GemCis) are often used as a first-line treatment. Interestingly, researchers have found an association between miRNAs and CCA therapy resistance. Examples include miR-210, which reduces sensitivity to gemcitabine, and miR-106b, which increases sensitivity to 5-fluorouracil sensitivity when overexpressed.
Importantly, novel therapies currently in development for the treatment of CCA are being designed to target miRNAs. By increasing expression of tumor suppressor miRNAs and downregulating expression of oncogenic miRNAs, targeted therapies may provide a powerful treatment option in the fight against CCA.
This sentiment was echoed in a recent expert consensus statement on CCA published in Nature Reviews Gastroenterology & Hepatology which noted that 50% of CCAs have genetic mutations which could be potential targets for miRNA-based therapy. The authors of the consensus statement note that “exploration of targeted therapies on a background of standard of care chemotherapy should be continued in CCA. In addition, combined efforts should be made to develop curative therapies.”
Although novel therapies hold promise, the authors of the Japanese review cite several preclinical studies which have demonstrated how tumor cell heterogeneity and the complexity of miRNA function in vivo have limited its clinical application thus far. Additionally, methods of drug delivery, determining an appropriately efficacious dose, and prediction of off-target effects are other obstacles that have prevented miRNA-based therapies from widespread adoption according to the review authors.
Despite the complexities surrounding miRNA-based diagnostics and therapeutics, continued research is urgently needed, given the alarming morbidity and mortality associated with CCA.
The authors of the review conclude by stating, “Further research and analyses of miRNAs will provide more evidence and novel insights into the pathogenesis of CCA and will prove to be useful for the diagnosis, therapy and prognosis prediction in patients with CCA.”
References
Shi T, Morishita A, Kobara H, Masaki T. The role of microRNAs in cholangiocarcinoma. Int J Mol Sci. 2021;22(14):7627. doi:10.3390/ijms22147627
Banales JM, Marin JJG, Lamarca A, et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol. 2020;17:557-588. doi:10.1038/s41575-020-0310-z
