Kunka Mohanram Ramkumar

Exploring the Role of Hypoxia and HIF-1α in the Intersection of Type 2 Diabetes Mellitus and Endometrial Cancer

Diabetes and Cancer are the most complex chronic diseases, accounting for significant global mortality and morbidity. The association between Type 2 DM (T2DM) and endometrial cancer (EC) is multifaced, sharing numerous risk factors, including insulin resistance, obesity, hypoxia, and oxidative stress. Hypoxia plays a vital role in T2DM pathogenesis by altering the insulin level and pancreatic β-cell failure through an imbalance between antioxidant enzymes and cellular oxidative levels, while chronic inflammation contributes to EC malignancy. HIF-1α is a potent transcription factor involved in modulating cellular responses to hypoxia within the disease environment. Targeting the HIF-1α signaling cascade, a major metabolic regulator may contribute to advanced therapeutic advances. This review focuses on the association between T2DM and EC, especially focusing on hypoxia and HIF signaling pathways. These intersect with key pathways involved in T2DM and EC pathology, such as insulin signaling, PI3K/AKT, mTOR pathway, MUC1/HIF-1α pathway, and hormonal imbalance. Understanding this complex relationship paves the way for future researchers to develop HIF-1α-targeted therapies that could lead to novel combination therapies to treat these comorbid conditions.

Exosomal miR16 induced by allyl isothiocyanate (AITC) inhibits tumor growth in cervical cancer via modulation of apoptotic and inflammatory pathways

The tumor micro-environment is a key determinant for promoting cancer cell growth and development with exosomal miRNAs emerging as key regulators of tumor growth and metastasis. miR16 is one well-established tumor suppressor miRNAs that induces apoptosis, while inhibiting angiogenesis and inflammation across various cancers. Herein, we investigated the role of exosomal miR16 in the cervical cancer microenvironment and its underlying molecular mechanisms. We treated human cervical cancer HeLa cells with Allyl Isothiocyanate (AITC) and observed the impact of miR16-enriched exosomes on human fibrosarcoma HT1080 cells. We found a significant increase of miR16 expression in AITC-treated HeLa cells and purified exosomes. When the exosomes were cultured with fibroblasts, miR16 expression was increased in fibroblast cells. Treatment with AITC-exposed HeLa exosomes induced increased Bax/Bcl2 ratio and downregulated PCNA, HIF-1α, SDF-1α, IL-6, and p22phox expression in fibroblasts. Remarkably, the knockdown of miR16 in fibroblasts inhibited the AITC-induced increase in the Bax/Bcl2 ratio and restored VEGF, PCNA, HIF-1α, SDF-1α, IL-6, and p22phox expression. In sum, our findings demonstrate the potential of AITC-mediated exosomal miR16 enrichment as an effective approach to inhibit cancer growth and development, and reveal a new potential for cancer management and therapy.