Estrogen and progestin regulate HIF-1α expression in ovarian cancer cell lines via the activation of Akt signaling transduction pathway

Hua, Keqin; Din, Jingxin; Cao, Qi; Feng, Weiwei; Zhang, Ying; Yao, Liangqin; Huang, Yan; Zhao, Yu-Qin; Yan, Feng

doi:10.3892/or_00000300

Cited by 16 publications

(3 citation statements)

References 17 publications

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“…This enhanced HIF-1α signaling significantly increased vascular endothelial growth factor (VEGF) expression in thyroid cancer cells, which could be due to enhanced binding of HIF-1α to the VEGF promoter. Multiple studies (Hua et al, 2009; (Rolfs, Kvietikova, Gassmann, & Wenger, 1997;Tacchini, Bianchi, Bernelli-Zazzera, & Cairo, 1999). Hepcidin and IRPs, the central mediators for systemic and intracellular iron homeostasis, are also regulated by HIFs.…”

Section: Discussionmentioning

confidence: 99%

“…This enhanced HIF‐1α signaling significantly increased vascular endothelial growth factor (VEGF) expression in thyroid cancer cells, which could be due to enhanced binding of HIF‐1α to the VEGF promoter. Multiple studies (Hua et al, ; Meyron‐Holtz et al, ) have implicated estrogen in the activation of HIF‐1α dependent VEGF production. HIFs play a key role in iron metabolism by regulating the expression of iron‐related proteins, such as DMT1 and FPN1 (Rolfs, Kvietikova, Gassmann, & Wenger, ; Tacchini, Bianchi, Bernelli‐Zazzera, & Cairo, ).…”

Section: Discussionmentioning

confidence: 99%

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Differential regulation of estrogen in iron metabolism in astrocytes and neurons

Tan

et al. 2018

Journal Cellular Physiology

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Previous studies have demonstrated an effect of estrogen on iron metabolism in peripheral tissues. The role of estrogen on brain iron metabolism is currently unknown. In this study, we investigated the effect and mechanism of estrogen on iron transport proteins. We demonstrated that the iron exporter ferroportin 1 (FPN1) and iron importer divalent metal transporter 1 (DMT1) were upregulated and iron content was decreased after estrogen treatment for 12 hr in primary cultured astrocytes. Hypoxia-inducible factor-1 alpha (HIF-1α) was upregulated, but HIF-2α remained unchanged after estrogen treatment for 12 hr in primary cultured astrocytes. In primary cultured neurons, DMT1 was downregulated, FPN1 was upregulated, iron content decreased, iron regulatory protein (IRP1) was downregulated, but HIF-1α and HIF-2α remained unchanged after estrogen treatment for 12 hr. These results suggest that the regulation of iron metabolism by estrogen in astrocytes and neurons is different. Estrogen increases FPN1 and DMT1 expression by inducing HIF-1α in astrocytes, whereas decreased expression of IRP1 may account for the decreased DMT1 and increased FPN1 expression in neurons.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Differential regulation of estrogen in iron metabolism in astrocytes and neurons

Tan

et al. 2018

Journal Cellular Physiology

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“…Both STC1 and STC2 promote epithelial to mesenchymal transition in hypoxic ovarian cancer cells and contribute to their invasion and metastasis as well ( 90 , 91 ). Additionally, estrogen and progestin can directly regulate HIF-1α through the PI3K/Akt-mTOR signaling pathway and contribute to tumor metastasis in ovarian cancer ( 92 ). In EOC, HIF-1α expression is upregulated and its increased expression is linked to poor survival ( 93 ).…”

Section: Hypoxia As a Feature Of Ovarian Cancer Progressionmentioning

confidence: 99%

Characterizing Endocrine Status, Tumor Hypoxia and Immunogenicity for Therapy Success in Epithelial Ovarian Cancer

et al. 2021

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Epithelial ovarian cancer is predominantly diagnosed at advanced stages which creates significant therapeutic challenges. As a result, the 5-year survival rate is low. Within ovarian cancer, significant tumor heterogeneity exists, and the tumor microenvironment is diverse. Tumor heterogeneity leads to diversity in therapy response within the tumor, which can lead to resistance or recurrence. Advancements in therapy development and tumor profiling have initiated a shift from a “one-size-fits-all” approach towards precision patient-based therapies. Here, we review aspects of ovarian tumor heterogeneity that facilitate tumorigenesis and contribute to treatment failure. These tumor characteristics should be considered when designing novel therapies or characterizing mechanisms of treatment resistance. Individual patients vary considerably in terms of age, fertility and contraceptive use which innately affects the endocrine milieu in the ovary. Similarly, individual tumors differ significantly in their immune profile, which can impact the efficacy of immunotherapies. Tumor size, presence of malignant ascites and vascular density further alters the tumor microenvironment, creating areas of significant hypoxia that is notorious for increasing tumorigenesis, resistance to standard of care therapies and promoting stemness and metastases. We further expand on strategies aimed at improving oxygenation status in tumors to dampen downstream effects of hypoxia and set the stage for better response to therapy.

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The Case for an Estrogen-iron Axis in Health and Disease

Hamad

Bajbouj

Taneera

2019

Exp Clin Endocrinol Diabetes

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Clinical and experimental evidence suggest that estrogen manipulates intracellular iron metabolism and that elevated levels of estrogen associate with increased systemic iron availability. This has been attributed to the ability of estrogen to suppress hepcidin synthesis, maintain ferroportin integrity and enhance iron release from iron-absorbing duodenal enterocytes and iron-storing macrophages and hepatocytes. These observations speak of a potential “estrogen-iron” axis that manipulates iron metabolism in response to hematologic (erythropoiesis) and non-hematologic (uterine growth, pregnancy, lactation) needs for iron. Such an axis could contribute to minimizing iron deficiency in premenopausal women and iron overload in postmenopausal women. It could also exacerbate iron overload and related clinical consequences including cancer, osteoporosis, cardiovascular complications and neurodegenerative symptoms, especially in postmenopausal women on hormonal replacement therapy. Understanding the role of estrogen in iron metabolism may shed some light on the pleotropic, but often paradoxical, roles of estrogen in human health and disease.

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Estrogen and progestin regulate HIF-1α expression in ovarian cancer cell lines via the activation of Akt signaling transduction pathway

Cited by 16 publications

References 17 publications

Differential regulation of estrogen in iron metabolism in astrocytes and neurons

Differential regulation of estrogen in iron metabolism in astrocytes and neurons

Characterizing Endocrine Status, Tumor Hypoxia and Immunogenicity for Therapy Success in Epithelial Ovarian Cancer

The Case for an Estrogen-iron Axis in Health and Disease

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