Key Insights on miR-216 as a Cancer Biomarker and Regulator

Introduction to miR-216 and Its Role in Cancer

MicroRNAs (miRNAs) are small noncoding RNA molecules that play a crucial role in post-transcriptional regulation of gene expression, influencing various biological processes including cell proliferation, differentiation, and apoptosis. Among these, microRNA-216 (miR-216), located on chromosome 2p16.1, has emerged as a significant player in cancer biology. Its dysregulation has been implicated in several malignancies, suggesting it serves as both a potential biomarker for cancer detection and a regulator of oncogenic pathways.

Research indicates that miR-216 can exhibit either tumor-suppressive or oncogenic properties, depending on the type of cancer. For instance, it has been observed to be downregulated in gliomas, breast cancers, and pancreatic cancers, acting as a tumor suppressor, while its expression is increased in acute myeloid leukemia (AML) and colorectal cancer, where it may function as an oncogene (Mondeali et al., 2025). The dual role of miR-216 in different tissues underscores its complex involvement in tumorigenesis and highlights its potential utility in clinical applications as a prognostic marker.

The Significance of miR-216 in Various Cancer Types

miR-216 has been extensively studied across multiple cancer types, revealing its involvement in critical pathways associated with tumor growth and metastasis. Below is a summary of its significance in various cancers:

Glioma

In glioma, miR-216 has been shown to be significantly downregulated. Studies suggest that its overexpression inhibits glioma cell proliferation and migration by targeting genes involved in oncogenic signaling pathways, such as AEG-1 and F11R (Li & Wang, 2018). This tumor-suppressive effect makes miR-216 a candidate for therapeutic targeting in glioma treatments.

Breast Cancer

In breast cancer, miR-216 is also downregulated, correlating with poorer clinical outcomes. It targets hexokinase 2 (HK2), a key player in the metabolic pathways of cancer cells. By inhibiting HK2, miR-216 can deactivate the mTOR signaling pathway, which is crucial for cell growth and proliferation (Liu et al., 2021). Thus, restoring miR-216 levels may present a novel therapeutic strategy to enhance the efficacy of existing breast cancer treatments.

Pancreatic Cancer

Pancreatic cancer is characterized by aggressive behavior and poor prognosis. miR-216’s downregulation in pancreatic tissues is associated with increased tumor proliferation and metastasis, potentially via its interactions with oncogenes like Kras and Janus kinase (Rachagani et al., 2015). By targeting these pathways, miR-216 may serve as a valuable prognostic marker for pancreatic cancer progression.

Colorectal Cancer

In colorectal cancer, elevated levels of miR-216 have been linked to enhanced cell proliferation and invasion, indicating its role as an oncogene in this context (Cai et al., 2021). Understanding the mechanisms through which miR-216 regulates these pathways may provide insights into novel therapeutic approaches.

Acute Myeloid Leukemia

Interestingly, miR-216 is upregulated in AML, and its expression correlates with certain mutations, such as U2AF1 and IDH1/2, which are associated with poorer patient outcomes (Zhang et al., 2018). This highlights the potential of miR-216 as a biomarker for disease stratification and treatment response in AML.

Mechanisms of miR-216 in Tumor Suppression and Oncogenesis

The functional dichotomy of miR-216, acting as either a tumor suppressor or oncogene, can be attributed to its regulation of various target genes involved in crucial signaling pathways.

Tumor Suppression

In cancers where miR-216 is downregulated, its loss leads to the upregulation of oncogenes and pro-tumorigenic pathways. For instance, in gliomas and breast cancers, the absence of miR-216 results in increased expression of genes that promote cell proliferation, survival, and migration. The targeting of these oncogenes by miR-216 restores the balance toward cell death and differentiation, thus inhibiting tumor growth.

Oncogenesis

Conversely, in cancers like AML and colorectal cancer, elevated levels of miR-216 may promote tumor growth by enhancing pathways that drive cell division and metastasis. The precise mechanisms remain under investigation, but it is hypothesized that miR-216 may interact with multiple pathways, including MAPK and PI3K/AKT signaling, which are pivotal in cancer cell survival and proliferation.

Clinical Implications of miR-216 for Cancer Diagnosis and Prognosis

The clinical relevance of miR-216 extends beyond its biological functions; it holds promise as a biomarker for cancer diagnosis and prognosis. Its expression levels correlate with tumor type, grade, and stage, providing insights into cancer behavior and patient outcomes.

Diagnostic Utility

The potential of miR-216 as a diagnostic marker is significant. In several studies, altered levels of miR-216 in serum or tissue samples have been associated with tumor presence and progression. For instance, its downregulation in pancreatic cancer tissues compared to adjacent non-tumor tissues offers a promising avenue for early detection strategies.

Prognostic Value

In terms of prognosis, the expression of miR-216 correlates with clinical outcomes. Lower levels of miR-216 in gliomas and breast cancers are associated with more aggressive disease and poorer survival rates, suggesting that it may serve as a prognostic indicator (Mondeali et al., 2025). Patients with high miR-216 expression in AML have shown better responses to treatment and improved overall survival, indicating its potential utility in guiding therapeutic decisions.

Future Directions in miR-216 Research and Therapeutic Applications

As research progresses, several future directions emerge for miR-216 in cancer therapy and management:

Targeted Therapies

Developing therapeutic strategies to restore miR-216 levels in cancers where it is downregulated could provide a novel approach to treatment. For instance, using miRNA mimics or delivery systems to enhance miR-216 expression may inhibit tumor growth and improve patient outcomes.

Liquid Biopsy Applications

The potential use of miR-216 in liquid biopsies represents a significant advance in non-invasive cancer diagnostics. Monitoring circulating miR-216 levels could enable real-time tracking of tumor dynamics and treatment responses, facilitating personalized treatment strategies.

Comprehensive Pathway Analysis

Further studies are needed to elucidate the complete network of genes and pathways regulated by miR-216. Understanding these interactions will provide insights into its role in various cancers and may uncover new therapeutic targets.

Conclusion

miR-216 stands out as a promising biomarker and therapeutic target in cancer biology. Its dual role as an oncogene and tumor suppressor highlights the complexity of miRNA regulation in cancer. As research continues, miR-216 may pave the way for novel diagnostic and therapeutic strategies, significantly impacting cancer treatment and patient care.

References

1. Mondeali, M., Mozaffari, F., Ghiasizadeh, P., Bakhti, S., Salehi, M., Kamali, N., & Rafat, M. (2025). miR-216 Is a Key Regulator and Potential Marker in Human Cancers. Advanced Biomedical Research. URL: https://pubmed.ncbi.nlm.nih.gov/12165296/

2. Zhang, T., Wu, D. H., Zhou, J. D., Li, X. X., Zhang, W., & Guo, H. (2018). Overexpression of miR‐216b: Prognostic and predictive value in acute myeloid leukemia. Journal of Cellular Physiology, 233(4), 2748-2855

3. Liu, T., Ye, P., Ye, Y., & Han, B. (2021). MicroRNA-216b targets HK2 to potentiate autophagy and apoptosis of breast cancer cells via the mTOR signaling pathway. International Journal of Biological Sciences, 17(29), 7034-4345. URL: https://doi.org/10.7150/ijbs.48933

4. Cai, Z., Suo, L., Huang, Z., & Isoflurane suppresses proliferation, migration, and invasion and facilitates apoptosis in colorectal cancer cells through targeting miR-216. Frontiers in Medicine, 8, 59261. URL: https://doi.org/10.3389/fmed.2021.658926

5. Rachagani, S., Macha, M. A., Menning, M. S., Dey, P. P., Pai, P. S., & Smith, L. M. (2015). Changes in microRNA (miRNA) expression during pancreatic cancer development and progression in a genetically engineered KrasG12D; Pdx1-Cre mouse (KC) model. Oncotarget, 5(29), 9512-9519. URL: https://doi.org/10.18632/oncotarget.5641

6. Li, Q., Wang, M., Wang, N., & Wang, Z. (2018). Downregulation of microRNA-216b contributes to glioma cell growth and migration by promoting AEG-1-mediated signaling. Biomed Pharmacother, 104, 420-427. URL: https://doi.org/10.1016/j.biopha.2018.05.048

7. Liu, T., Ye, P., Ye, Y., & Han, B. (2021). MicroRNA-216b targets HK2 to potentiate autophagy and apoptosis of breast cancer cells via the mTOR signaling pathway. International Journal of Biological Sciences, 17(29), 7034-4345. URL: https://doi.org/10.7150/ijbs.48933

8. Zhang, T., Wu, D. H., Zhou, J. D., Li, X. X., Zhang, W., & Guo, H. (2018). Overexpression of miR‐216b: Prognostic and predictive value in acute myeloid leukemia. Journal of Cellular Physiology, 233(4), 2748-2855