Aging is associated with increased brain iron through cortex-derived hepcidin expression.

Iron is an essential molecule for biological processes, but its accumulation can lead to oxidative stress and cellular death. Due to its oxidative effects, iron accumulation is implicated in the process of aging and neurodegenerative diseases. However, the mechanism for this increase in iron with aging, and whether this increase is localized to specific cellular compartment(s), are not known. Here, we measured the levels of iron in different tissues of aged mice, and demonstrated that while cytosolic non-heme iron is increased in the liver and muscle tissue, only the aged brain cortex exhibits an increase in both the cytosolic and mitochondrial non-heme iron. This increase in brain iron is associated with elevated levels of local hepcidin mRNA and protein in the brain. We also demonstrate that the increase in hepcidin is associated with increased ubiquitination and reduced levels of the only iron exporter, ferroportin-1 (FPN1). Overall, our studies provide a potential mechanism for iron accumulation in the brain through increased local expression of hepcidin, and subsequent iron accumulation due to decreased iron export. Additionally, our data support that aging is associated with mitochondrial and cytosolic iron accumulation only in the brain and not in other tissues.

Augmenter of liver regeneration regulates cellular iron homeostasis by modulating mitochondrial transport of ATP-binding cassette B8.

Chronic loss of Augmenter of Liver Regeneration (ALR) results in mitochondrial myopathy with cataracts; however, the mechanism for this disorder remains unclear. Here, we demonstrate that loss of ALR, a principal component of the MIA40/ALR protein import pathway, results in impaired cytosolic Fe/S cluster biogenesis in mammalian cells. Mechanistically, MIA40/ALR facilitates the mitochondrial import of ATP-binding cassette (ABC)-B8, an inner mitochondrial membrane protein required for cytoplasmic Fe/S cluster maturation, through physical interaction with ABCB8. Downregulation of ALR impairs mitochondrial ABCB8 import, reduces cytoplasmic Fe/S cluster maturation, and increases cellular iron through the iron regulatory protein-iron response element system. Our finding thus provides a mechanistic link between MIA40/ALR import machinery and cytosolic Fe/S cluster maturation through the mitochondrial import of ABCB8, and offers a potential explanation for the pathology seen in patients with ALR mutations.

Interleukin-6 as an enhancer of anti-angiogenic therapy for ovarian clear cell carcinoma.

Ovarian clear cell carcinoma (OCCC) is a subtype of epithelial ovarian cancer (EOC) that is associated with elevated interleukin-6 (IL-6) expression, resistance to chemotherapy, and increased mortality. Although bevacizumab (Bev) is a widely used anti-angiogenic agent for EOC, the efficacy of Bev and the role of IL-6 in modulating angiogenesis in OCCC are unknown. We performed tube formation assays using human umbilical vein endothelial cells (HUVEC) cultured in OCCC cell-conditioned medium and using cells directly co-cultured with OCCC cells. We observed that IL-6 inhibition significantly mitigated the ability of Bev to impede tube formation in both cases. Furthermore, IL-6 blockade disrupted the anti-angiogenic efficacy of Bev and its concomitant anti-tumor activity. In addition, IL-6 inhibition resulted in a significant increase in angiopoietin-1 (Ang1) secretion and decreased vascular endothelial growth factor (VEGF) expression. Clinical specimens also exhibited this reciprocal relationship between IL-6 and Ang1 expression. Finally, depletion of Ang1 abrogated the effects of IL-6 inhibition on Bev activity, demonstrating that IL-6 supports the anti-angiogenic activity of Bev by suppressing Ang1 expression and promoting dependence on VEGF for angiogenesis. Altogether, our data suggest that OCCC tumors with high IL-6 levels are candidates for Bev therapy.

Study of the Awareness of Adoption as a Family-Building Option Among Oncofertility Stakeholders in Japan.

Purpose: The oncofertility decision tree was developed by the oncofertility consortium as a tool to support healthcare professionals and patients through the complicated process of deciding the most appropriate fertility preservation strategy for patients with cancer. Various strategies include oocyte retrieval, oocyte donation, use of a gestational carrier and adoption. However, differences in the cultural and legal landscape present serious barriers to utilizing some of these strategies in Japan. Patients and Methods: We surveyed Japanese oncofertility stakeholders including 60 cancer survivors, 27 oncology facilities, 78 reproductive medicine facilities and 15 adoption agencies by a questionnaire to characterize awareness among oncofertility stakeholders in Japan about parenting options including adoption to inform work to establish guidelines for decision-making by cancer survivors in an oncofertility. Results: Our results indicate that oncologists and reproductive endocrinologists in Japan have an insufficient understanding of adoption that prevents them from adequately informing their patients. Japanese cancer survivors self-describe a lack in confidence in finding a suitable partner and raising a child. Contrastingly, of the 9 adoption agencies which responded, no agency included being a cancer survivor as a criterion for disqualification and 4 of 9 (44%) adoption agencies reported at least 1 adoption to a cancer survivor in the last year. Conclusion: Our work demonstrates that a cancer survivor's medical history itself is not a hurdle to adoption and investment in patient-provider education could be a viable strategy to improve the utilization of adoption as a fertility preservation strategy in Japan.

Study of the Awareness of Adoption as a Family-Building Option Among Oncofertility Stakeholders in Japan.

PURPOSE: The oncofertility decision tree was developed by the oncofertility consortium as a tool to support healthcare professionals and patients through the complicated process of deciding the most appropriate fertility preservation strategy for patients with cancer. Various strategies include oocyte retrieval, oocyte donation, use of a gestational carrier and adoption. However, differences in the cultural and legal landscape present serious barriers to utilizing some of these strategies in Japan. PATIENTS AND METHODS: We surveyed Japanese oncofertility stakeholders including 60 cancer survivors, 27 oncology facilities, 78 reproductive medicine facilities and 15 adoption agencies by a questionnaire to characterize awareness among oncofertility stakeholders in Japan about parenting options including adoption to inform work to establish guidelines for decision-making by cancer survivors in an oncofertility. RESULTS: Our results indicate that oncologists and reproductive endocrinologists in Japan have an insufficient understanding of adoption that prevents them from adequately informing their patients. Japanese cancer survivors self-describe a lack in confidence in finding a suitable partner and raising a child. Contrastingly, of the 9 adoption agencies which responded, no agency included being a cancer survivor as a criterion for disqualification and 4 of 9 (44%) adoption agencies reported at least 1 adoption to a cancer survivor in the last year. CONCLUSION: Our work demonstrates that a cancer survivor's medical history itself is not a hurdle to adoption and investment in patient-provider education could be a viable strategy to improve the utilization of adoption as a fertility preservation strategy in Japan.

MicroRNA-34a/IL-6R pathway as a potential therapeutic target for ovarian high-grade serous carcinoma.

Accumulating evidence has indicated that microRNAs play a critical role in the pathogenesis of human cancers. microRNA-34a (miR-34a) has been shown to be a key regulator of tumor suppression by targeting several cancer-related signals, including the interleukin-6 receptor (IL-6R)/Signal Transducers and Activator of Transcription 3 (STAT3) signaling pathway. Previously, we determined that miR-34a expression was frequently reduced in high-grade serous carcinoma (HGSC), the major subtype of epithelial ovarian cancer (EOC). Considering that the IL-6R/STAT3 signaling pathway is upregulated and believed to be a potential therapeutic target in EOC, we investigated the biological significance of reduced miR-34a expression in HGSC with regard to IL-6R signaling. Additionally, we evaluated the viability of miR-34a as a therapeutic application for HGSC both in vitro and in vivo. Accordingly, we found that the ectopic expression of miR-34a significantly reduced tumor proliferation and invasion through downregulation of IL-6R expression, suggesting that reduced miR-34a expression might play an important role in the malignant potential of HGSC through upregulation of the IL-6R/STAT3 signaling pathway. Moreover, we demonstrated that replacement of miR-34a reduced tumorigenicity of HGSC in vivo. Therefore, this study may provide the rationale for miR-34a replacement as a promising therapeutic strategy for HGSC.