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Acquired Evolution of Mitochondrial Metabolism Regulated by HNF1B in Ovarian Clear Cell Carcinoma

1
Department of Gynecology and Obstetrics, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
2
Department of Gynecology, Shiga General Hospital, Moriyama, Shiga 524-8524, Japan
*
Author to whom correspondence should be addressed.
Academic Editor: Kylie Gorringe
Cancers 2021, 13(10), 2413; https://doi.org/10.3390/cancers13102413
Received: 2 March 2021 / Revised: 12 May 2021 / Accepted: 13 May 2021 / Published: 17 May 2021
(This article belongs to the Special Issue Targeted Therapy for Ovarian Cancer)
Ovarian clear cell carcinoma (CCC) exhibits unique characteristics, including slow growth, glycogen accumulation in the cytoplasm, and poor prognosis for stress resistance. Several molecular targeting agents have failed to treat ovarian CCC. Recent reports have identified metabolic alterations through HNF1B, which is highly expressed in ovarian CCC. The Warburg effect, GSH synthesis, and mitochondrial regulation occur in CCC. The metabolic behaviors of ovarian CCC resemble the evolution of life to survive in stressful environments. Understanding the fundamental biology of ovarian CCC might help in the development of novel therapeutic strategies.
Clear cell carcinoma (CCC) of the ovary exhibits a unique morphology and clinically malignant behavior. The eosinophilic cytoplasm includes abundant glycogen. Although the growth is slow, the prognosis is poor owing to resistance to conventional chemotherapies. CCC often arises in endometriotic cysts and is accompanied by endometriosis. Based on these characteristics, three clinical questions are considered: why does ovarian cancer, especially CCC and endometrioid carcinoma, frequently occur in endometriotic cysts, why do distinct histological subtypes (CCC and endometrioid carcinoma) arise in the endometriotic cyst, and why does ovarian CCC possess unique characteristics? Mutations in AT-rich interacting domain-containing protein 1A and phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit alpha genes may contribute to the carcinogenesis of ovarian CCC, whereas hepatocyte nuclear factor-1-beta (HNF1B) plays crucial roles in sculpting the unique characteristics of ovarian CCC through metabolic alterations. HNF1B increases glutathione synthesis, activates anaerobic glycolysis called the Warburg effect, and suppresses mitochondria. These metabolic changes may be induced in stressful environments. Life has evolved to utilize and control energy; eukaryotes require mitochondria to transform oxygen reduction into useful energy. Because mitochondrial function is suppressed in ovarian CCC, these cancer cells probably acquired further metabolic evolution during the carcinogenic process in order to survive stressful environments. View Full-Text
Keywords: ovarian clear cell carcinoma; metabolism; mitochondrion; Warburg effect; glutathione synthesis ovarian clear cell carcinoma; metabolism; mitochondrion; Warburg effect; glutathione synthesis
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MDPI and ACS Style

Yamaguchi, K.; Kitamura, S.; Furutake, Y.; Murakami, R.; Yamanoi, K.; Taki, M.; Ukita, M.; Hamanishi, J.; Mandai, M. Acquired Evolution of Mitochondrial Metabolism Regulated by HNF1B in Ovarian Clear Cell Carcinoma. Cancers 2021, 13, 2413. https://doi.org/10.3390/cancers13102413

AMA Style

Yamaguchi K, Kitamura S, Furutake Y, Murakami R, Yamanoi K, Taki M, Ukita M, Hamanishi J, Mandai M. Acquired Evolution of Mitochondrial Metabolism Regulated by HNF1B in Ovarian Clear Cell Carcinoma. Cancers. 2021; 13(10):2413. https://doi.org/10.3390/cancers13102413

Chicago/Turabian Style

Yamaguchi, Ken, Sachiko Kitamura, Yoko Furutake, Ryusuke Murakami, Koji Yamanoi, Mana Taki, Masayo Ukita, Junzo Hamanishi, and Masaki Mandai. 2021. "Acquired Evolution of Mitochondrial Metabolism Regulated by HNF1B in Ovarian Clear Cell Carcinoma" Cancers 13, no. 10: 2413. https://doi.org/10.3390/cancers13102413

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