CBX2 identified as driver of anoikis escape and dissemination in high grade serous ovarian cancer

Wheeler, Lindsay J.; Watson, Zachary L.; Qamar, Lubna; Yamamoto, Tomomi M.; Post, Miriam D.; Berning, Amber; Spillman, Monique A.; Behbakht, Kian; Bitler, Benjamin G.

doi:10.1038/s41389-018-0103-1

Cited by 65 publications

(54 citation statements)

References 46 publications

(55 reference statements)

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“…In HCC tissues, strong increases in higher levels of CBX2 expression at the mRNA and protein levels were found, and CBX2 expression at the transcriptional level was positively correlated with cancer stages and grades [41]. In this study, IHC staining demonstrated that CBX2 expression was obviously elevated at the translational level in serous ovarian cancer tissues compared with normal ovarian tissues, which was similar to a previous finding [40]. Recently, Zheng et al [42] found a link between increased CBX2 expression and worse prognosis of breast cancer patients.…”

Section: Discussionsupporting

confidence: 91%

“…Elevated expression of CBX2 at both the transcriptional and translational levels was observed in aggressive prostate cancer [13]. Notably, previous studies showed that in primary high-grade serous ovarian carcinoma, CBX2 protein expression was obviously increased compared with that in normal cancer tissues [40]. In HCC tissues, strong increases in higher levels of CBX2 expression at the mRNA and protein levels were found, and CBX2 expression at the transcriptional level was positively correlated with cancer stages and grades [41].…”

Section: Discussionmentioning

confidence: 93%

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The Prognostic Value of the Chromobox Family in Human Ovarian Cancer

Pan

Song

et al. 2020

J. Cancer

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Ovarian cancer is one of the most lethal gynecologic tumors in women and has a poor prognosis. The purpose of our study was to identify new prognostic markers in ovarian cancer. We examined the prognostic roles of mRNA expression of the chromobox (CBX) family in patients with ovarian cancer utilizing the Kaplan-Meier plotter database. The prognostic values and expression levels of CBX members associated with prognosis were further evaluated using KM plotter in diverse subgroups and immunohistochemistry (IHC) analysis in ovarian carcinoma. The results revealed that elevated CBX1-3 mRNA expression may predict poor overall survival (OS) and progression-free survival (PFS) outcomes in patients with ovarian cancer. Notably, in women with ovarian cancer, increased CBX1 mRNA expression was linked to a short OS in all stages and in the grade II and grade III subgroups. Additionally, CBX2 and CBX3 were strongly related to short OS in stage III+IV patients, and a link between high CBX3 mRNA expression and unfavorable OS in grade II patients was observed. High expression levels of CBX1 and CBX3 were significantly associated with chemotherapy resistance in ovarian cancer patients. IHC staining showed that the CBX1-3 proteins were upregulated in serous ovarian carcinoma tissues compared with normal ovarian tissues. Therefore, our results indicated that CBX1-3 could be attractive biomarkers for predicting poor prognosis of ovarian cancer.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 93%

The Prognostic Value of the Chromobox Family in Human Ovarian Cancer

Pan

Song

et al. 2020

J. Cancer

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“…Significantly downregulated genes enriched for terms related to the cell membrane, adhesion, and ECM in both extracted and treated cells. Previous studies have shown that cancer cells resisting apoptosis in nonadherent conditions are also more chemoresistant (Eguchi et al, 2015; Foley et al, 2015; Wheeler et al, 2018). Additionally in ovarian cancer, nonadherent cancer spheroids either created in vitro or isolated from in vivo ascites fluid also demonstrate enhanced chemoresistance (Hirst et al, 2018; Liao et al, 2014; Wheeler et al, 2018).…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies have shown that cancer cells resisting apoptosis in nonadherent conditions are also more chemoresistant (Eguchi et al, 2015; Foley et al, 2015; Wheeler et al, 2018). Additionally in ovarian cancer, nonadherent cancer spheroids either created in vitro or isolated from in vivo ascites fluid also demonstrate enhanced chemoresistance (Hirst et al, 2018; Liao et al, 2014; Wheeler et al, 2018). Moreover, ovarian cancer spheroids are thought to be a unique subpopulation of tumor cells with self‐renewal capability and enhanced chemoresistance (Liao et al, 2014).…”

Section: Resultsmentioning

confidence: 99%

Immobilization rapidly selects for chemoresistant ovarian cancer cells with enhanced ability to enter dormancy

Lam

Aguirre‐Ghiso

Geller

et al. 2020

Biotech & Bioengineering

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Around 20–30% of ovarian cancer patients exhibit chemoresistance, but there are currently no methods to predict whether a patient will respond to chemotherapy. Here, we discovered that chemoresistant ovarian cancer cells exhibit enhanced survival in a quiescent state upon experiencing the stress of physical confinement. When immobilized in stiff silica gels, most ovarian cancer cells die within days, but surviving cells exhibit hallmarks of single‐cell dormancy. Upon extraction from gels, the cells resume proliferation but demonstrate enhanced viability upon reimmobilization, indicating that initial immobilization selects for cells with a higher propensity to enter dormancy. RNA‐seq analysis of the extracted cells shows they have signaling responses similar to cells surviving cisplatin treatment, and in comparison to chemoresistant patient cohorts, they share differentially expressed genes that are associated with platinum‐resistance pathways. Furthermore, these extracted cells demonstrate greater resistance to cisplatin and paclitaxel, despite being proliferative. In contrast, serum starvation and hypoxia could not effectively select for chemoresistant cells upon removal of the environmental stress. These findings demonstrate that ovarian cancer chemoresistance and the ability to enter dormancy are linked, and immobilization rapidly distinguishes chemoresistant cells. This platform could be suitable for mechanistic studies, drug development, or as a clinical diagnostic tool.

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“…We reasoned therefore that CBX2 regulates the expression of multiple genes involved in these processes, among which the EMT mediates the hematogenous dissemination of carcinomas (36). Moreover, evidence indicates that CBX2 regulates autophagy, apoptosis, and the EMT (8). Overexpression of WNT5B, which was co-ordinately expressed with CBX2 in our mRNA microarray analysis of OSCC, contributes to the EMT and is associated with increased hematogenous metastasis in lung cancer and pancreatic cancer (37).…”

Section: Discussionmentioning

confidence: 90%

Chromobox 2 Expression Predicts Prognosis After Curative Resection of Oesophageal Squamous Cell Carcinoma

Ueda

Kanda

Sato

et al. 2020

Cancer Genomics Proteomics

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Background/Aim: To investigate the function of chromobox 2 (CBX2) in oesophageal squamous cell carcinoma (OSCC). Materials and Methods: We used real-time quantitative reverse transcription PCR (qRT-PCR) and immunohistochemistry to determine CBX2 expression levels in 13 human OSCC cell lines and clinical specimens of two independent cohorts of patients with OSCC. Results: PCR array analysis revealed that CBX2 was co-ordinately expressed with WNT5B in OSCC cell lines. RT-qPCR analysis of clinical samples revealed a high tumour-specific CBX2 expression compared with normal oesophageal tissues. High CBX2 expression was significantly associated with shorter disease-specific survival, hematogenous recurrence, and overall recurrence. Analysis of tissue microarrays of one cohort revealed that patients with higher CBX2 levels tended to have a shorter disease-specific survival. Conclusion: CBX2 overexpression in OSCC tissues may serve as a novel biomarker for predicting survival and hematogenous recurrence. The main histopathological subtypes of oesophageal carcinoma, the sixth leading cause of cancer-related mortality worldwide (1), are adenocarcinoma and oesophageal squamous cell carcinoma (OSCC). The latter is the predominant subtype in Asia and Africa (2). OSCC is generally associated with poor prognosis, mainly because of its high potential to metastasize, which accounts for its dismal overall survival rate of <40%, despite radical treatment (3). A primary goal of efforts to improve the management of OSCC and patients' outcomes is to develop methods that accurately predict the risk of recurrence and survival after curative oesophageal resection (4, 5). Specific biomarkers that predict the recurrence pattern of OSCC, particularly for hematogenous recurrence after radical treatment, will likely contribute to improving patients' outcomes and are therefore the focus of our research. We the aim to identify novel biomarkers, we first focused on the chromobox 2 (CBX2) gene, a member of the chromobox (CBX) gene family, because of its reported association with certain cancers (6-8). CBX2 encodes a subunit of the polycomb group (PcG), whose members form complexes that mediate homeostasis (9). These proteins regulate the expression of numerous genes that control the maintenance, differentiation and proliferation of adult stem cells and cancer cells (10). Biochemical characterization led to the categorization of PcG complexes into two subtypes: Polycomb repressive complex (PRC) 1 and PRC2 (6, 11, 12). The CBX gene family comprises CBX2, CBX4, CBX6, CBX7 and CBX8, which encode components of PRC1 (11). PRC1 members are associated with tumourigenesis. For example, CBX4 plays important roles in cellular proliferation and in the repair of DNA damage in certain human tumours (13, 14). CBX6 was identified as a susceptibility loci by a genome-wide association study on bladder cancer (15). Numerous studies have shown that CBX7 is specifically 391 This article is freely accessible online.

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CBX2 identified as driver of anoikis escape and dissemination in high grade serous ovarian cancer

Cited by 65 publications

References 46 publications

The Prognostic Value of the Chromobox Family in Human Ovarian Cancer

The Prognostic Value of the Chromobox Family in Human Ovarian Cancer

Immobilization rapidly selects for chemoresistant ovarian cancer cells with enhanced ability to enter dormancy

Chromobox 2 Expression Predicts Prognosis After Curative Resection of Oesophageal Squamous Cell Carcinoma

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