Expression of the Bric-a-Brac Tramtrack Broad Complex Protein NAC-1 in Cervical Carcinomas Seems to Correlate with Poorer Prognosis

Yeasmin, Sabina; Nakayama, Kentaro; Ishibashi, Mariko; Katagiri, Atsuko; Iida, Kouji; Purwana, Indri N.; Nakayama, Naomi; Miyazaki, Kohji

doi:10.1158/1078-0432.ccr-07-4085

Cited by 39 publications

(43 citation statements)

References 23 publications

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“…Reduction of NAC1 expression resulted in apoptosis in the NAC1 expressing cell lines Ishikawa, HHUA, and JHEM2, indicating that NAC1 was essential for proliferation and survival of these cell lines. These results are similar to those obtained in our previous experiments in ovarian and cervical cancer cell lines (17,20). Besides its critical role in maintaining cell proliferation and survival, NAC1 overexpression could also enhance cellular proliferation.…”

Section: Discussionsupporting

confidence: 91%

“…NAC1 is a transcription repressor that is involved in self renewal and the maintenance of pluripotency in embryonic stem cells (18). NAC1 is significantly overexpressed in several types of human carcinomas (17), where it plays a critical role in maintaining tumor cell proliferation and survival (17,(19)(20)(21). Recently, we showed that NAC1 is essential for the proliferation of normal cyclic endometrial glandular cells and is up-regulated by estrogen (22).…”

Section: Introductionmentioning

confidence: 99%

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NAC1, a potential stem cell pluripotency factor expression in normal endometrium, endometrial hyperplasia and endometrial carcinoma

Nakayama¹

2010

Int J Oncol

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Abstract. The purpose of this study was to investigate the role of NAC1 in the development of endometrial cancer. NAC1 expression and localization were assessed with immunohistochemistry in the normal cyclic human endometrium, hyperplastic endometrium, and endometrial cancer. Expression of NAC1 in the glandular cells was significantly higher in the early and mid proliferative phases than in the other menstrual phases, endometrial hyperplasia, and endometrial carcinoma. NAC1 expression was down-regulated during endometrial carcinogenesis. There were significant correlations between positive NAC1 expression and pathological grade (P=0.037). No significant associations were found between NAC1 expression and the other clinicopathological characteristics including patient age, FIGO staging, depth of myometrial invasion, pelvic lymph node metastasis, lymphovascular space invasion, menopause, or body mass index. NAC1 gene knockdown inhibited cell growth and induced apoptosis in Ishikawa, HHUA, and JHEM2 cell lines, all of which overexpressed NAC1. Ectopic overexpression of the NAC1 gene stimulated cell proliferation in the HEC1B, and JHEM1 endometrial cancer cell lines, which have lower endogenous NAC1 expression. Endometrial carcinomas with NAC1 overexpression are clinically aggressive, high-grade carcinomas. Therefore, detection of NAC1 overexpression in endometrial cancers may identify patients who will benefit from NAC1 targeted therapy.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

NAC1, a potential stem cell pluripotency factor expression in normal endometrium, endometrial hyperplasia and endometrial carcinoma

Nakayama¹

2010

Int J Oncol

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“…NAC1 expression was essential for growth and survival in the normal endometrium. Because NAC1 is considered to have oncogenic potential (11,14,20), the current findings may provide new insight into understanding the mechanism behind estrogen-induced endometrial carcinogenesis.…”

Section: Discussionmentioning

confidence: 90%

“…Recently, we reported that NAC1, a gene with oncogenic potential, was associated with gynecologic tumors (11,14,20).…”

Section: Discussionmentioning

confidence: 99%

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Expression of a BTB/POZ Protein, NAC1, Is Essential for the Proliferation of Normal Cyclic Endometrial Glandular Cells and Is Up-regulated by Estrogen

Ishibashi

Nakayama

Yeasmin

et al. 2009

Clinical Cancer Research

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Purpose: The purpose of this study was to investigate the expression and localization of NAC1, a member of the BTB/POZ gene family in the human cyclic endometrium. Experimental Design: NAC1expression in normal cyclic endometrium was assessed by immunohistochemistry, and data on clinical variables were collected by retrospective chart review. To elucidate the molecular mechanisms of NAC1expression in the normal endometrium endometrial carcinoma cell lines (Ishikawa, HHUA; ER+, PR+) and primary cultured normal endometria were tested in a sex steroid induction assay and a NAC1knockdown assay using siRNA. Results: Expression of NAC1in glandular cells was significantly higher in the early and mid proliferative phases than in the other menstrual phases. Both NAC1RNA and protein expression were up-regulated by treatment with 10 nmol/L17h-Estradiol (E2) in Ishikawa, HHUA and primary cultured normal endometrial cells.The estrogen receptor antagonist ICI 182,780 significantly attenuated E2-induced NAC1 expression. NAC1 gene knockdown inhibited cell growth and induced apoptosis in Ishikawa, HHUA, and normal endometria, all of which expressed NAC1. Furthermore, NAC1siRNA significantly abrogated estrogen-driven cellular proliferation in Ishikawa, HHUA, and primary cultured normal endometrial cells, whereas the control siRNA had no effect on cell growth in any of these cells. Conclusions: These findings suggest that NAC1 is functionally involved in E2-induced cell growth of the normal endometrial glandular cells. Because NAC1 is thought to have oncogenic potential, the current findings may provide new insight into the mechanism of estrogen induced endometrial carcinogenesis.Proliferation and differentiation of the human endometrium are controlled by ovarian steroids via their receptors. Estrogen stimulates the proliferation of both glandular and stromal cells, whereas progesterone inhibits their growth. Various aspects of hormone-induced proliferation and differentiation of the endometrium have been investigated. Studies have examined up-and down-regulation of steroid receptors (1, 2) and the role of growth factors or cytokines (3). The sex steroidinduced events are generally believed to occur via estrogen receptors (ER) and progesterone receptors. The molecular pathways downstream of these receptors that eventually promote the transcription of target genes, however, have not been fully elucidated. Steroid receptor cofactors have recently been identified as important molecules intervening between the receptors and target genes. These cofactors are now functionally divided into two subclasses, i.e., coactivators and corepressors. Cofactors are either activators or repressors for other transcription factors and participate in a transcriptional factor cascade of positive and negative regulators. Only a few factors, however, are directly involved in normal endometrial cycles.The genes of the BTB/POZ family participate in several cellular functions including proliferation, apoptosis, transcription control, and cell morpho...

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CRM197 reverses paclitaxel resistance by inhibiting the NAC‐1/Gadd45 pathway in paclitaxel‐resistant ovarian cancer cells

Tang

Zheng

et al. 2019

Cancer Medicine

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Heparin‐binding epidermal growth factor‐like growth factor (HB‐EGF) is a new promising target for the treatment of ovarian cancer. Our previous study showed that cross‐reacting material 197 (CRM197), a specific HB‐EGF inhibitor, significantly reverses resistance against paclitaxel in paclitaxel‐resistant ovarian cancer cells. However, the mechanism of the effect of CRM197 on the reversion of paclitaxel resistance was unclear. In this study, in vitro and in vivo data suggested that CRM197 treatment sensitized paclitaxel‐resistant ovarian cancer cells to paclitaxel, at least in part, via nucleus accumbens‐1 (NAC‐1) and its downstream pathway, DNA damage‐inducible 45‐γ interacting protein (Gadd45gip1)/growth arrest and DNA damage‐inducible 45 (Gadd45), in A2780/Taxol and SKOV3/Taxol cells. The results also showed that CRM197 activated the proapoptotic JNK/p38MAPK pathway to enhance caspase‐3 activity and apoptosis by downregulation of the NAC‐1/Gadd45gip1/Gadd45 pathway, leading to reversion of paclitaxel resistance in A2780/Taxol and SKOV3/Taxol cells. This study provides the first mechanism through which CRM197 significantly reverses resistance against paclitaxel by modulating the NAC‐1/Gadd45gip1/Gadd45 pathway in paclitaxel‐resistant ovarian cancer cells, and the mechanism of HB‐EGF inhibition as a novel therapeutic strategy for patients with paclitaxel‐resistant ovarian cancer.

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Expression of the Bric-a-Brac Tramtrack Broad Complex Protein NAC-1 in Cervical Carcinomas Seems to Correlate with Poorer Prognosis

Cited by 39 publications

References 23 publications

NAC1, a potential stem cell pluripotency factor expression in normal endometrium, endometrial hyperplasia and endometrial carcinoma

NAC1, a potential stem cell pluripotency factor expression in normal endometrium, endometrial hyperplasia and endometrial carcinoma

Expression of a BTB/POZ Protein, NAC1, Is Essential for the Proliferation of Normal Cyclic Endometrial Glandular Cells and Is Up-regulated by Estrogen

CRM197 reverses paclitaxel resistance by inhibiting the NAC‐1/Gadd45 pathway in paclitaxel‐resistant ovarian cancer cells

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