Introduction to HMGB3 in Oncology

High mobility group box 3 (HMGB3) has emerged as a central player in HMGB3 cancer therapy resistance and the maintenance of stemness across various human malignancies. This protein belongs to the HMG-box family and regulates crucial biological processes like transcription, chromatin remodeling, and DNA repair. While HMGB3 remains vital for embryonic development, its expression usually drops significantly in healthy adult tissues. However, researchers have observed its aberrant upregulation in several cancers, including leukemia, breast, bladder, and colorectal cancer. High levels of this protein often correlate with a poor clinical prognosis. Consequently, understanding its molecular mechanisms is essential for developing next-generation oncology treatments.

Mechanisms of HMGB3 Cancer Therapy Resistance

The multifaceted nature of HMGB3 allows it to orchestrate resistance through several pathways. Specifically, HMGB3 promotes the survival of cancer stem cells (CSCs), which are notoriously resistant to standard treatments. By maintaining these cell populations, the protein ensures tumor regrowth even after initial chemotherapy or radiotherapy. Furthermore, HMGB3 enhances the efficiency of DNA damage repair. It facilitates the processing of DNA interstrand crosslinks and double-strand breaks, thereby neutralizing the effects of platinum-based drugs and radiation. Additionally, this protein modulates cell death pathways and helps remodel the tumor microenvironment to favor immune evasion.

Clinical Significance and Future Directions

Identifying HMGB3 as a pivotal orchestrator provides a novel avenue for clinical intervention. Because it is silenced in most normal adult tissues, it represents a highly selective therapeutic target. Inhibiting HMGB3 could potentially sensitize resistant tumors to chemotherapy, targeted therapy, and immunotherapy. Moreover, its close association with poor outcomes in gastric and hematological cancers makes it a valuable prognostic biomarker. Ultimately, overcoming HMGB3 cancer therapy resistance may lead to significantly improved survival rates and more effective personalized treatment strategies for patients with advanced malignancies.

Frequently Asked Questions

How does HMGB3 contribute to chemoresistance?

HMGB3 enhances DNA damage repair pathways and promotes cancer stemness. These actions allow tumor cells to survive the cytotoxic effects of drugs like cisplatin and continue proliferating.

Why is HMGB3 considered a promising therapeutic target?

Since HMGB3 is significantly downregulated in normal adult tissues but highly expressed in many cancers, targeting it could selectively kill cancer cells while minimizing side effects on healthy tissues.

What cancers are most affected by HMGB3 upregulation?

Abnormal HMGB3 expression is frequently found in leukemia, as well as breast, bladder, colorectal, and gastric cancers, where it often signifies a more aggressive disease course.

Disclaimer: This content is for informational and educational purposes only and does not constitute medical advice or a professional relationship. Always seek the advice of a qualified healthcare provider regarding any medical condition or treatment. Refer to the latest local and national guidelines for clinical practice.

References

Zhang J et al. HMGB3: A pivotal orchestrator of therapy resistance and cancer stemness in human malignancies (Review). Oncol Rep. 2026 Jun undefined. doi: undefined. PMID: 41930588.

Mukherjee A, et al. High-Mobility Group Box Protein 3 (HMGB3) Facilitates DNA Interstrand Crosslink Processing and Double-Strand Break Repair in Human Cells. Int J Mol Sci. 2025 Sep 4;26(17):8942. doi: 10.3390/ijms26178942.

Ma Y, et al. HMGB3 promotes the malignant phenotypes and stemness of epithelial ovarian cancer through the MAPK/ERK signaling pathway. Biol Chem. 2024 Jul 12. doi: 10.1515/hsz-2024-0142.