The Role of Hepatocyte Nuclear Factor-1β in the Pathogenesis of Clear Cell Carcinoma of the Ovary

Kobayashi, Hiroshi; Yamada, Yoshihiko; Kanayama, Seiji; Furukawa, Naoto; Noguchi, Taketoshi; Shoji, Hirokazu; Yoshida, Shozo; Sakata, Mariko; Sado, Toshiyuki; Oi, Hidekazu

doi:10.1111/igc.0b013e3181a19eca

Cited by 60 publications

(78 citation statements)

References 118 publications

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“…Clarification of the mechanism of these metabolic characteristics may yield a new strategy to overcome the disease. Several studies have considered the mechanism of facilitated glycogen accumulation of OCCC (12,13), but a conclusion has not yet been reached. Some studies have found that the glycogen accumulation in several kinds of tumor cells was accelerated under hypoxic conditions (14)(15)(16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

Hypoxia promotes glycogen synthesis and accumulation in human ovarian clear cell carcinoma

et al. 2012

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Abstract. Ovarian clear cell carcinoma (OCCC) has several significant characteristics based on molecular features that are distinct from those of ovarian high-grade serous carcinoma. Cellular glycogen accumulation is the most conspicuous feature of OCCC and in the present study its metabolic mechanism was investigated. The amount of glycogen in cells cultured under hypoxia increased significantly and approximately doubled after 48 h (P<0.01) compared to that under normoxic conditions. Periodic acid-Schiff positive staining also demonstrated intracellular glycogen storage. Western blot analysis revealed that HIF1α, which was overexpressed and stabilized under hypoxic conditions, led to an increase in the levels of cellular glycogen synthase 1, muscle type (GYS1), and conversely to a decrease in inactive phosphorylated GYS1 at serine (Ser) 641. Additional increases were observed in both protein phosphatase 1, which dephosphorylates and thereby induces GYS1 enzyme activity, and glycogen synthase kinase 3 beta (GSK3β) phosphorylated at Ser9, which is inactive on phosphorylation of GYS1 and subsequently induces its enzyme activity. By contrast, the level of PYGM-b decreased. These results indicated that the glycogen accumulation under a hypoxic environment resulted in the promotion of glycogen synthesis, but did not lead to inhibition of glycogen degradation and/or consumption. Under hypoxic conditions, HAC2 cells showed activation of the PI3K/AKT pathway caused by a mutation in exon 20 of PIK3CA, encoding the catalytic subunit p110α of PI3K. The resulting activation of AKT (phosphoSer473) also plays a role as a central enhancer in glycogen synthesis through suppression of GSK3β via phosphorylation at Ser9. Hypoxia decreased the cytocidal activity of cisplatin and doxorubicin to various degrees. In conclusion, the hypoxic conditions together with HIF1 expression and stabilization increased the intracellular glycogen contents and resistance to the anticancer drugs.

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Section: Introductionmentioning

confidence: 99%

Hypoxia promotes glycogen synthesis and accumulation in human ovarian clear cell carcinoma

et al. 2012

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“…Ovarian clear cell carcinoma is diagnosed at an early stage in B60% of patients; however, it carries a worse prognosis because resistance to conventional cytotoxic chemotherapeutic agents is common even with early disease. [5][6][7] Identification of the molecular pathways, which confer chemoresistance in ovarian clear cell carcinoma is essential for the development of novel targeted therapeutic agents.…”

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confidence: 99%

Loss of ARID1A expression is related to shorter progression-free survival and chemoresistance in ovarian clear cell carcinoma

et al. 2012

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Recently, the ARID1A gene has been identified as a novel tumor suppressor in ovarian clear cell carcinoma. The prognostic significance of the loss of ARID1A expression is not known. The current study was designed to evaluate whether ARID1A was a prognostic factor for progression, survival, and chemoresistance in ovarian clear cell carcinoma. A total of 60 patients, who were surgically treated for primary ovarian clear cell adenocarcinoma, were enrolled. Surgical specimens were examined for ARID1A protein expression by immunohistochemistry. The correlations between the loss of ARID1A expression and clinicopathological characteristics, prognosis, and chemosensitivity were investigated. Loss of ARID1A expression was identified in 9 (15.0%) of 60 ovarian clear cell carcinoma samples. Loss of ARID1A staining intensity (0 þ ) was more frequently found in cells of clear cell carcinomas than in high-grade serous carcinomas (Po0.01). Loss of ARID1A expression was significantly correlated with advanced FIGO stage and high CA125 levels (P ¼ 0.02, 0.01). There were no significant correlations between loss of ARID1A expression and patient age, status of residual tumor, Ki-67 labeling index, or the status of endometriosis. Loss of ARID1A correlated with shorter progression-free survival of patients with clear cell carcinomas treated with platinum-based chemotherapy (Po0.01). Loss of ARID1A expression tended to correlate with shorter overall survival in patients with ovarian clear cell carcinomas treated with platinum-based chemotherapy. When data were stratified for the multivariate analysis, only the loss of ARID1A expression remained a significant (P ¼ 0.03) predictor of reduced progressionfree survival. Of the 60 patients with ovarian clear cell carcinomas, 14 patients had measurable residual tumor after primary cytoreductive surgery. Tumors with loss of ARID1A expression were more likely to be chemoresistant than tumors with positive ARID1A expression (100.0 vs 40.0%, P ¼ 0.04). This study demonstrates that loss of ARID1A in ovarian clear cell carcinoma is a negative prognostic factor in patients treated with platinum-based chemotherapy. Measurement of ARID1A expression may be a method to predict resistance to platinum-based chemotherapy in patients with ovarian clear cell carcinoma.

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“…This suggests biological differences between clear cell carcinomas that arise in association with adenofibroma vs. endometriosis. Recent genome-wide expression analyses have demonstrated the specific expression of hepatocyte nuclear factor (HNF)-1β in endometriosis and clear cell carcinoma, but not endometrioid adenocarcinoma, suggesting that early differentiation into the clear cell lineage occurs in the endometriosis with HNF-1β overexpression (32). The HNF-1β-dependent pathway provides new insights into the regulation of apoptosis, the cell cycle, glycogen synthesis and chemoresistance (32).…”

Section: Clear Cell Carcinoma Of the Ovarymentioning

confidence: 99%

“…Recent genome-wide expression analyses have demonstrated the specific expression of hepatocyte nuclear factor (HNF)-1β in endometriosis and clear cell carcinoma, but not endometrioid adenocarcinoma, suggesting that early differentiation into the clear cell lineage occurs in the endometriosis with HNF-1β overexpression (32). The HNF-1β-dependent pathway provides new insights into the regulation of apoptosis, the cell cycle, glycogen synthesis and chemoresistance (32). It has been reported that HNF-1β gene might play a role in carcinogenesis, pathogenesis, and the pathophysiology of clear cell carcinoma of the ovary (32).…”

Section: Clear Cell Carcinoma Of the Ovarymentioning

confidence: 99%

Identification of multiple pathways involved in the malignant transformation of endometriosis (Review)

et al. 2012

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Abstract. The association between endometriosis and malignant transformation has often been described in the medical literature. A search was conducted between 1966 and 2010 through the English language literature (online Medline PubMed database) using the keywords endometriosis combined with malignant transformation. The search revealed an increase in reports describing endometriosis and malignancy. Approximately 1.0% of women with endometriosis have lesions that undergo malignant transformation. The malignant processes that are associated with endometriosis may be classified into three groups: i) epithelial ovarian cancers (endometrioid adenocarcinoma and clear cell carcinoma), ii) other Müllerian-type tumors, including Müllerian-type mucinous borderline tumor and serous borderline tumor and iii) sarcomas such as adenosarcoma and endometrial stromal sarcoma in the female pelvic cavity. Persistent oxidative stress induced by endometriosis-dependent hemorrhage may be associated with carcinogenesis. In conclusion, the malignant transformation of endometriosis has multiple pathways of development and may share a common pathogenic mechanism; iron-induced oxidative stress derived from repeated hemorrhage.

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The Role of Hepatocyte Nuclear Factor-1β in the Pathogenesis of Clear Cell Carcinoma of the Ovary

Abstract: This review summarizes recent advances in the HNF-1beta and its target genes; the potential challenges to the understanding of carcinogenesis, pathogenesis, and pathophysiology of CCC; and a possible novel model is proposed.

Cited by 60 publications

References 118 publications

Hypoxia promotes glycogen synthesis and accumulation in human ovarian clear cell carcinoma

Hypoxia promotes glycogen synthesis and accumulation in human ovarian clear cell carcinoma

Loss of ARID1A expression is related to shorter progression-free survival and chemoresistance in ovarian clear cell carcinoma

Identification of multiple pathways involved in the malignant transformation of endometriosis (Review)

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