Inhibition of Cell Death and Induction of G2 Arrest Accumulation in Human Ovarian Clear Cells by HNF-1β Transcription Factor: Chemosensitivity Is Regulated by Checkpoint Kinase CHK1

Shinmoto, Hiroshi; Sudo, Tamotsu; Shimada, Kaoru; Uekuri, Chiharu; Tsuji, Yoriko; Kanayama, Seiji; Naruse, Katsuhiko; Yamada, Yoshihiko; Konishi, Noboru; Kobayashi, Hiroshi

doi:10.1097/igc.0000000000000136

Cited by 17 publications

(53 citation statements)

References 19 publications

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“…ATR and CHEK1 are synthetic lethal pairs between two proteins in the same pathway and maintain cancer cell survival under replication stress (10,29). CCC have been assumed to demonstrate an increased reliance on the HNF-1β-CHEK1 axis for cell survival (49). Significant genes involved in synthetic lethality with CHEK1 are reported to be ATR, MYC, TP53, WEE1 and CDKN1A (29,(61)(62)(63).…”

Section: Discussionmentioning

confidence: 99%

“…These analyses revealed a significant representation in the cell cycle regulation and DNA repair pathways (18)(19)(20). Overexpression of HNF-1β (>90%), CHEK1, X-ray repair cross complementing (XRCC) 5, cyclin (CCN) E1 and CDC28 protein kinase regulatory subunit 1B (CKS1B) is a common genetic change in CCC (28,29,(47)(48)(49). A novel role for transcription factor HNF-1β in DDR was identified (49).…”

Section: Candidate Mutated Genes For Enhancing the Therapeutic Ratio mentioning

confidence: 99%

“…Overexpression of HNF-1β (>90%), CHEK1, X-ray repair cross complementing (XRCC) 5, cyclin (CCN) E1 and CDC28 protein kinase regulatory subunit 1B (CKS1B) is a common genetic change in CCC (28,29,(47)(48)(49). A novel role for transcription factor HNF-1β in DDR was identified (49). CCC cells are dependent on the HNF-1β-CHEK1 axis for cell survival (15).…”

Section: Candidate Mutated Genes For Enhancing the Therapeutic Ratio mentioning

confidence: 99%

“…These were predicted as synthetic lethality gene partners for PARP inhibitors (26,27,(56)(57)(58). Overexpression of oncogenes ERBB2, FGFR2 and MYC in CCC cells accelerates the DNA replication stress, accumulates DNA DSBs and associates with synthetic lethality to PARP1 inhibitors (46)(47)(48)(49)(50)(51)(52). A contextual synthetic lethality exists between the combined inhibition of ERBB2 and PARP (46).…”

Section: Candidate Mutated Genes For Enhancing the Therapeutic Ratio mentioning

confidence: 99%

“…CCC cells are dependent on the HNF-1β-CHEK1 axis for cell survival (15). CCC cells exhibit the upregulation of HNF-1β expression and accumulate G1/S cell cycle arrest, which results in the constitutive expression of the activated CHEK1 in response to DNA damage (49). DNA repair protein XRCC5 functions as the repair of DNA DSBs by NHEJ (50).…”

Section: Candidate Mutated Genes For Enhancing the Therapeutic Ratio mentioning

confidence: 99%

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Candidate synthetic lethality partners to PARP inhibitors in the treatment of ovarian clear cell cancer

et al. 2017

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Abstract. Inhibitors of poly(ADP-ribose) polymerase (PARP) are new types of personalized treatment of relapsed platinum-sensitive ovarian cancer harboring BRCA1/2 mutations. Ovarian clear cell cancer (CCC), a subset of ovarian cancer, often appears as low-stage disease with a higher incidence among Japanese. Advanced CCC is highly aggressive with poor patient outcome. The aim of the present study was to determine the potential synthetic lethality gene pairs for PARP inhibitions in patients with CCC through virtual and biological screenings as well as clinical studies. We conducted a literature review for putative PARP sensitivity genes that are associated with the CCC pathophysiology. Previous studies identified a variety of putative target genes from several pathways associated with DNA damage repair, chromatin remodeling complex, PI3K-AKT-mTOR signaling, Notch signaling, cell cycle checkpoint signaling, BRCA-associated complex and Fanconi's anemia susceptibility genes that could be used as biomarkers or therapeutic targets for PARP inhibition. BRCA1/2, ATM, ATR, BARD1, CCNE1, CHEK1, CKS1B, DNMT1, ERBB2, FGFR2, MRE11A, MYC, NOTCH1 and PTEN were considered as candidate genes for synthetic lethality gene partners for PARP interactions. When considering the biological background underlying PARP inhibition, we hypothesized that PARP inhibitors would be a novel synthetic lethal therapeutic approach for CCC tumors harboring homologous recombination deficiency and activating oncogene mutations. The results showed that the majority of CCC tumors appear to have indicators of DNA repair dysfunction similar to those in BRCA-mutation carriers, suggesting the possible utility of PARP inhibitors in a subset of CCC.

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Section: Discussionmentioning

confidence: 99%

Section: Candidate Mutated Genes For Enhancing the Therapeutic Ratio mentioning

confidence: 99%

Section: Candidate Mutated Genes For Enhancing the Therapeutic Ratio mentioning

confidence: 99%

Section: Candidate Mutated Genes For Enhancing the Therapeutic Ratio mentioning

confidence: 99%

Section: Candidate Mutated Genes For Enhancing the Therapeutic Ratio mentioning

confidence: 99%

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Candidate synthetic lethality partners to PARP inhibitors in the treatment of ovarian clear cell cancer

et al. 2017

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Proteomic analysis reveals mechanisms underlying increased efficacy of bleomycin by photochemical internalization in bladder cancer cells

Gederaas,

Sharma,

Mbarak

et al. 2023

Mol. Omics

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Napsin A, Hepatocyte Nuclear Factor-1-Beta (HNF-1β), Estrogen and Progesterone Receptors Expression in Arias-Stella Reaction

Ip¹,

Wang²,

Wong³

et al. 2019

American Journal of Surgical Pathology

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Background: The Arias-Stella reaction (ASR) can mimic endometrial clear cell carcinoma (ECCC) in small biopsies, especially when drug or pregnancy history is unknown. A panel of immunohistochemical markers comprising napsin A, hepatocyte nuclear factor-1-beta (HNF-1β), estrogen and progesterone receptors (ER, PR) has been found useful in confirming a diagnosis of ECCC. However, the detailed characterization of how expression of this combination of markers in the ECCC mimics ASR has yet to be thoroughly evaluated. Design: The frequency and extent of napsin A, HNF-1β, ER, and PR expression in ASR were assessed in a large series. For napsin A, any cytoplasmic staining was considered positive while only nuclear staining was deemed to be positive for HNF-1β, ER, and PR. Immunohistochemical histoscores based on the intensity and extent of staining were calculated. Results: Forty cases were gestational and 10 were nongestational ASR. In 19 (38%), the reaction was extensive and involved >50% of the glands. A stromal decidual change was found in 31 (77.5%) of the gestational and 3 (30%) of the nongestational cases. Napsin A was positive in all gestational and 8 of 10 (80%) nongestational ASR. All ASR showed HNF-1β expression. ER expression was reduced in 37 (92.5%) and lost in 3 (7.5%) gestational ASR, and reduced in 9 (90%) and lost in 1 (10%) of nongestational ASR. None of the ASR in our series expressed PR. Conclusions: Naspin A and HNF-1β were frequently expressed in both gestational and nongestational ASR, and ER expression was usually either reduced or loss. Interpretation of these markers in small biopsies containing atypical clear cells should be made with caution.

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Inhibition of Cell Death and Induction of G2 Arrest Accumulation in Human Ovarian Clear Cells by HNF-1β Transcription Factor: Chemosensitivity Is Regulated by Checkpoint Kinase CHK1

Abstract: The chemoresistance of CCA may be due to aberrant retention of the G2 checkpoint through overexpression of HNF-1β. This is the first study demonstrating cell cycle regulation and chemosensitization by a CHK1 inhibitor in CCA.

Cited by 17 publications

References 19 publications

Candidate synthetic lethality partners to PARP inhibitors in the treatment of ovarian clear cell cancer

Candidate synthetic lethality partners to PARP inhibitors in the treatment of ovarian clear cell cancer

Proteomic analysis reveals mechanisms underlying increased efficacy of bleomycin by photochemical internalization in bladder cancer cells

Napsin A, Hepatocyte Nuclear Factor-1-Beta (HNF-1β), Estrogen and Progesterone Receptors Expression in Arias-Stella Reaction

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