Increased High Mobility Group Protein A2/SMAD3 Relates to Ovarian Cancer Progression

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Ovarian Cancer, HMGA2, Drug Resistance


Introduction: The high mortality associated with ovarian cancer is generally related to the development of drug-resistant disease. HMGA2 protein, a member of the high-mobility group AT-hook (HMGA) family of non-histone chromatin binding factors, is overexpressed in high-grade serous ovarian and tubal carcinomas, though little is known about its contribution to disease progression and drug resistance. We sought to assess whether compositional changes in HMGA2 production were associated with ovarian cancer progression.

Methods: We performed computational characterization of HMGA2 protein disorder, aggregation propensity and interactability. Cultures of established human ovarian cancer cell lines and immortalized ovarian surface epithelial cells were subjected to MTS growth assays, western immunoblotting and immunoprecipitation analyses for HMGA2, SMAD3 and SNAIL1 expression. Lastly, urine samples from healthy controls, women with benign gynecologic disease and women with ovarian cancer were analyzed by western immunoblotting for HMGA2 and SMAD3 levels.

Results: HMGA2 is a highly disordered protein with the potential to bind multiple protein partners, including SMAD3. Characteristics of HMGA2 binding partners suggested possible recruitment of HMGA2 for extracellular transport. We verified overexpression and secretion of HMGA2 and SMAD3 in cultures of ovarian cancer cells, especially with emergence of drug resistance. In agreement with computational analyses, we demonstrated that HMGA2 and SMAD3 protein can associate into a larger protein complex in ovarian cancer cells. Lastly, elevated levels of HMGA2 and SMAD3 were found in urine samples from ovarian cancer patients.

Conclusion: Our data suggest that the presence of and/or changes in the levels of a unique HMGA2/SMAD3 protein complex might serve as a useful biomarker and/or therapeutic target for ovarian cancer.

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Journal of Gynecology Research, v. 1, issue 1