Research ArticleExperimental Studies

Polycomb Protein BMI-1 as a Potential Therapeutic Target in Mucinous Ovarian Cancer

SALEM ABOBAKER, HAGEN KULBE, ELIANE T. TAUBE, SILVIA DARB-ESFAHANI, ROLF RICHTER, CARSTEN DENKERT, PAUL JANK, JALID SEHOULI and ELENA IOANA BRAICU
Anticancer Research April 2022, 42 (4) 1739-1747; DOI: https://doi.org/10.21873/anticanres.15650

Abstract

Background/Aim: Mucinous ovarian carcinoma (mOC) is a rare subtype with distinct clinical characteristics and biological behavior that differentiate them from other epithelial ovarian cancers. This study aimed to evaluate BMI-1 expression as a potential target for therapeutic approaches in advanced stage mOC. Materials and Methods: We performed gene set, as well as transcription factor enrichment analysis and immunohistochemistry assessing of the BMI-1 protein levels in tissue specimens of eighteen mucinous ovarian cancer patients. To validate the clinical relevance of the findings, we performed cell viability assays and western blot analysis utilizing high-grade serous (HGSC) and mOC cell lines. Results: BMI1 expression was not significantly associated with patient age, FIGO stage, lymph node status, and family history. With regard to progression-free survival, there was also no significant association (p=0.418). Cell viability was significant decreased in response to carboplatin in HGSC cells TYK-nu and OVHASO, and in mOC cell lines COV644 and EFO-27. Western blot analysis demonstrated various expression levels across all cell lines. Conclusion: BMI-1 could be a useful potential therapeutic target in some ovarian cancer patients, including mOC patients.

Key Words:

Epithelial ovarian cancer (EOC) is a histologically, clinically, and molecularly diverse disease, and includes five main subtypes of ovarian cancer - high grade serous, low grade serous, clear cell, endometrioid, and mucinous (1, 2). For many years, ovarian cancer therapy followed a one-size-fits-all principle with debulking surgery and platinum-based chemotherapy as main pillars. Recently, PARP inhibitors (PARPi) were introduced as maintenance therapy in high grade ovarian cancer patients following first line or relapse chemotherapy (3–5). Despite initial complete clinical response to surgery and first-line chemotherapy, 70% of the patients with advanced stage cancer will relapse and subsequently die due to their disease (6).

Mucinous ovarian cancer (mOC) is a rare histological sub-type, accounting approximately for 3% of all EOC (7–10). Primary mucinous ovarian cancer is distinct from other EOCs in both presentation and patient outcome (11, 12); there is one hypothesis that mOC develops along a continuum from benign cysts into borderline tumors and finally into invasive carcinomas. In contrast to early-stage patients that generally have a good prognosis, patients where the cancer has spread beyond the ovaries exhibit particularly poor outcome and response to conventional ovarian cancer chemotherapy (13–15).

Differentiation on a morphological or immunohistochemical basis between colorectal and ovarian mucinous tumors is rather difficult. Staining for biomarker CDX2, CA19-9 and CEA share positive expression levels with colorectal carcinomas (CRC, while only the ratio of CK7/CK20 positivity might be different between mOC and CRC, making in advanced stages, certain assignment to origin of primary tumors more difficult (16–18).

Due to morphologic and immunohistochemical similarities between mOC and gastrointestinal tumors, chemotherapy regimens used in (CRC) have been analyzed on mucinous ovarian cancer (mOC) patients. The Gynocologic Oncology Group (GOG) and the Gynecologic Cancer Intergroup (GCIG) conducted a phase III randomized clinical study (GOG241), comparing carboplatin and paclitaxel versus oxaliplatin and capecitabine, with and without bevacizumab in patients with either primary or recurrent mOC (19). The study discontinued early due to recruitment difficulties. Moreover, innovative therapy options such as PARP inhibitors are most likely ineffective, since BRCA1 or BRCA2 mutations and deficiency in homologous recombination are not common traits in mOC (20). Due to their rarity, different clinical behavior, and different molecular characteristics, mOC patients are usually excluded from the majority of the clinical trials, increasing the gap to an efficient treatment for this histological subtype.

In recent years, the Polycomb complex protein BMI-1, a member of polycomb repressive complex 1, has been recently discussed as a novel therapeutic approach and is known to be over-expressed in colorectal, breast, prostate, and ovarian cancers (21, 22). The rationale behind this is that BMI-1 is an important cancer stem cell factor that contributes to cancer progression, initiation, and chemoresistance (23, 24). Therefore, the purpose of this study was to evaluate BMI-1 expression as a potential target for therapeutic approaches in advanced stage mOC.

Materials and Methods

Analysis of gene enrichment. The microarray datasets GSE6008 were downloaded from the GEO (25). The data were analyzed using Bioconductor 1.9 (26), running on R 2.6.0 (27). Probeset expression measures were calculated using the Affymetrix package’s Robust Multichip Average (RMA) default method (28). An empirical Bayes t-test (limma program) was used to analyze differential gene expression between mOC samples and other EOC subtype groups (29). The p-values were adjusted for multiple testing using the Benjamini–Hochberg method (30). Differentially expressed probes were chosen based on a false discovery rate (FDR) of less than 0.05. GeneGO processes within the MetaCore pathway tool were utilized to determine enrichment by dividing probes into positive and negative fold change lists (GeneGo, Inc., Saint Joseph, MI, USA). Transcription factors (TFs) enrichment analysis was performed using the gene lists of TF targets from the CHIP Enrichment Analysis (ChEA) database, which describes the binding of 135 TFs to experimentally validated target genes (31). The function GeneSetTest from the limma package was used to assess whether TFs were significantly associated with mOC. The analysis utilizes a hypergeometric distribution to decide the most enriched gene set.

Cell lines and cell culture features. Mucinous cell line EFO-27 (from DSMZ Braunschweig, Germany), the derivation and source of which has been described in the DSMZ database (32), COV664 supplied by Public Health England’s European Collection of Authenticated Cell Cultures, and MACS, a kind gift from Prof. Dr. Michael J. Birrer, Center for Cancer Research, the Gillette Center for Gynecologic Oncology, Massachusetts General Hospital and Harvard Medical School. HGSC cell lines (TYK-nu, OVCAR3, Kuramochi, SNU-119, OVHASO, and OVKATE) were obtained from a global biological resource center (ATCC, Manassas, VA, USA). Cell lines were cultured in RPMI Medium 1640 (Life Technologies, Gibco, Warrington, UK), containing 10% fetal bovine serum (FBS), at 37°C in 5% CO2 with 95% air.

Histopathological examination and study population. In total, 18 patients with primary mucinous ovarian carcinoma from the Tumor Bank Ovarian Cancer-Charité Cohort were selected. As part of the selection process, we excluded metastasis from another primary, and obtained the clinical, pathological, and immunohistochemical characteristics of each tumor from the data bank. Two spots of formalin-fixed paraffin-embedded FFPE tissue were contained in the tissue microarrays (TMAs) that were created as previously described (33).

Cell viability assay. Cells were plated in triplicate with a density of 3,000 cells/well in 96-well plates, which were incubated at 37°C. carboplatin (in various concentrations) was used to treat the cells for 48 h. After the addition of 10 μl of WST-1 reagent into each well, incubation was performed for a further 120 min and finally, absorbance was assessed at 450 nm and 670 nm, which are representative of the detection wavelength and reference wavelength, respectively. A blank control was also used.

Immunohistochemistry. Immunohistochemical (IHC) staining was performed on tissue microarrays (TMAs) constructed as described previously (33). The slides were boiled in citrate buffer (PH 6.0) within a pressure cooker for 5 min, and immunostaining for BMI-1 was performed by using a specific antibody against BMI1 protein (Anti-BMI-1, clone F6, Monoclonal Antibody- Millipore, Darmstadt, Germany), diluted (1:200) and incubated on the slides for 1 h at room temperature. Bound antibodies were visualized using the DAKO Real Detection System and DAB+ (3, 3’-diaminobenzidine; DAKO, Glostrup, Denmark) was used as a chromogen. Finally, the slides were co-stained with hematoxylin.

Evaluation of immunostaining. A light microscope was used for the visualization of BMI-1 protein expression in stained tissues. The definition adopted for BMI-1 immunostaining was an immunoreactivity scoring system (IRS) score including staining quantity and intensity analogue as used with breast cancer.

The IRS value (0-12), was obtained following the multiplication of staining intensity and the percentage of positive cells (34). IRS Scores were grouped into negative, weak, moderate, and strong based on a previously described scale (33).

Western blot. Total cell lysate was prepared in RIPA buffer (Sigma-Aldrich, St. Louis, MO, USA). Measurement of protein concentration was performed using BCA Protein assay reagent kit (Pierce Biotechnology, Waltham, MA, USA) and immunoblotting was performed using standard protocols (35). Briefly, cell extracts (15 μg) were run on a 10% SDS acrylamide gel and transferred to a nylon membrane. The membrane was blocked for 1 h (4°C in PBS with 0.1% Tween and 10% milk powder) and probed overnight using a primary antibody (Anti-BMI-1, clone F6 Millipore). A horseradish peroxidase-conjugated secondary antibody was then used for detection (1:2,000 dilution) at room temperature for 1 h. Protein concentration equivalence was confirmed by the anti-β-actin antibody.

Statistical analysis. Version 25.0 IBM SPSS software (SPSS, IBM company, Chicago, IL, USA), was utilized for the statistical analysis. Spearman coefficient and Fisher’s exact test were utilized in the assessment of BMI-1 tumor expression correlation. p-Value <0.05 was considered significant. Progression-free survival (PFS) was estimated with the Kaplan–Meier method.

Results

In silico data analysis. Since mOC displays distinct gene expression profiles compared with other EOC subtypes, we used comparative bioinformatics methods to predict potential therapeutic targets. These were based on publicly available gene expression array datasets from ovarian cancer biopsies of various subtypes, including mucinous, high-grade serous, and clear cell.

First, we found that mucinous cancers are associated with the RAS oncogenic pathway signature as defined by Bild et al. (36). Using a MetaCore™ gene set enrichment analysis (GSEA) of the differentially expressed genes detected between the EOC subtypes, we found a strong association between mucinous gene expression patterns and processes relating to glucose metabolism, cell cycle, and hormone receptor signaling pathways. There was also a significant association with genes involved in the EGFR, NOTCH, WNT, and TGFb1 signaling pathways. However, genes involved in inflammation and immune response were significantly impaired (p<0.0001).

We investigated the activity of 135 TFs based on experimentally validated target genes from the CHIP Enrichment Analysis (ChEA) database (31). Of these 135 TFs, the target genes of 21 were significantly enriched in biopsies of mEOC. Among these were SMAD2 and 3, as well as CTNNB1 and TCF4, as downstream targets of the TGFb1 and WNT signaling pathways, respectively (37, 38). Transcripts regulated by HNF4α were also significantly elevated. HNF4α has been demonstrated to be a useful marker for histological and cytological diagnosis of ovarian mucinous tumors (36). Notably, TF activity of BMI1 and ESR1 were most significantly increased in tumors of the mOC subtype (Figure 1).

Figure 1.
Figure 1.

Enrichment plots for the transcriptional regulator of pluripotency BMI1 and estrogen receptor signaling pathway, ESR1. Gene expression profiles from biopsies of mucinous epithelial ovarian cancer were compared with other subtypes of epithelial ovarian cancer.

We performed TF enrichment analysis as above using the significantly differentially expressed genes between mucinous and high-grade serous cell lines. BMI1 and ESR1 were highly enriched in mOC cells. Moreover, we performed Principal Component Analysis (PCA) to assess the similarity of gene expression profiles of mucinous cell lines (in blue) and high grade serous ovarian cancer (HGSOC) cell lines (in red) (Figure 2). This illustrated that mucinous cell lines are very similar to each other and distinct from the other cell lines included in this analysis.

Figure 2.
Figure 2.

Principal component analysis of gene expression profiles from 14 ovarian cancer cell lines using the gene expression signatures from the Cancer Cell Line Encyclopedia (CCLE).

BMI-1 expression. Immunohistochemical assessment on paraffin sections of mOCs was also performed and the staining procedure for BMI1 was optimized. As shown, nuclear staining ranged from negative to strong (Figure 3A and B, respectively) in malignant cells. Strong BMI-1 expression was observed in 22% of samples, moderate expression in 16.7%, low in 38.9%, and negative in 22.2% (Figure 3C). Subsequently, we investigated correlations between these signals and the clinical variable of International Federation of Gynecology and Obstetrics (FIGO) but observed no correlation (p=0.583; Fisher’s Exact Test) (Figure 4). Furthermore, there was no correlation between BMI1 and lymph node (LN) status (p=0.850; Pearson Chi-Square), family history of gastric or colon cancer (p=0.417 Fisher’s Exact Test) as well as the age at first diagnosis (p=0.659 Mann-Whitney U-Test) or other clinical pathological factors.

Figure 3.
Figure 3.

Immunohistochemical staining for BMI-1 in mucinous ovarian cancer tissues. (A) BMI-1 immunoreactivity negative. (B) Strong BMI-1 immunoreactivity. (C) Immunoreactivity scoring system distribution of BMI-1.

Figure 4.
Figure 4.

A correlation between BMI-1 expression in mucinous epithelial ovarian cancer and International Federation of Gynecology and Obstetrics (FIGO) stages (p=0.583).

Effects of carboplatin on mucinous and HGS ovarian cancer cell viability. The standard of care for patients with advanced ovarian cancer involves first-line chemotherapy with carboplatin and paclitaxel. Therefore, the cell viability of various HGSOC and mOC cells was assessed by WST-1 assays after 72 h of treatment with carboplatin. A significant decrease in cell viability in response to carboplatin occurred in HGSOC TYK-nu and OVHASO, as well as mOC COV644 and EFO-27 cells (Figure 5A and B) in a dose-dependent manner. On the other hand, OVKATE, Kuramochi, SNU-11, and MACS cells were relatively resistant to carboplatin treatment (Figure 5C).

Figure 5.
Figure 5.

Cell viability assays of carboplatin. WAST1 assay showing the effect of different concentrations of carboplatin on a panel of HGSOC cells (A) and mOC cells (B) after 48 h of treatment. IC50 of carboplatin in different cell lines (C). BMI-1 protein levels by western immunoblotting in a panel of HGSOC and mOC cell lines (D).

Western blot analysis. HGSC and mOC ovarian cancer cell lines (N=6 and N=3, respectively) were assessed for the abundance of BMI-1 protein expression using western blot analysis. We identified a pronounced expression of BMI-1 protein in Kuramochi, Tyk-nu, and MACS. Slight expression was shown in OVCAR-3, OVHASHO, and COV644. Meanwhile, very low expression was seen in SNU-119, OVKATE, and EFO-27 (Figure 5D).

Clinicopathologic characteristics. As seen in Table I, the study included 18 mOC female patients ranging from 24 to 83 years with a median age of 56 years, purposed for analysis and assessment of BMI-1 protein expression in relation to clinical-pathological variables.

View this table:
Table I.

Association of BMI-1 expression with the clinicopathologic characteristics of patient variables.

Survival. Although Kaplan–Meier analysis revealed no significant difference between BMI-1low and BMI1high mOCs, a slight trend for patients with BMI1low was observed. The rates were shown to be 81.8% and 71.4% for tumors with low and high BMI-1 expression, respectively (p=0.418 Log Rank) (Figure 6).

Figure 6.
Figure 6.

Kaplan–Meier curve of progression-free survival of mucinous ovarian cancer with BMI-1low and BMI-1high expression (p=0.418).

Discussion

More knowledge on the molecular biology of EOC, including better understanding of the role of genetic alterations in BRCA1, BRCA2, K-RAS, p53, and PTEN, is needed to create more effective therapies (39), due the fact that current classical therapies, including chemotherapy with platinum and paclitaxel, are of limited value. BRCA1 and BRCA2 mutations are thought to play a significant role in the development of serous EOC, but not mOC (40). Moreover, mutations in TP53 have been found in about 96% of HGSOC but just 16% of mucinous tumors. Furthermore, in contrast to HGSOC, the K-RAS oncogene is typically over-expressed in mOC. Moreover, KRAS mutations are prevalent in 43–46% of mOCs (41). A recent study found that HER2 amplification occurred in 35% of mOC patients; however, HER2 expression is known to be relatively rare in EOC (42, 43). In summary, it is important to identify biomarkers that are associated with pathophysiological behaviors of mOC to explain recurrence and mechanisms of chemoresistance, for better treatment of patients with mOC.

In our study, we analyzed mOC in comparison to high-grade serous ovarian cancer by the PCA method, using gene expression profiling of cell lines, and chemotherapy resistance in vitro. Pathway enrichment analysis identified the Notch pathway and BMI-1 to be expressed differently in high-grade OCs and mOCs.

BMI1 has been described as an oncoprotein in several studies (44). BMI-1’s oncogenic activity has been observed in epithelial malignancies such as ovarian cancer, and has been found to induce down-regulation of p16INK4a, which is involved in controlling ovarian epithelial cancer proliferation, apoptosis, self-renewal, and even chemoresistance (45). Due to the similarities between colorectal and mOC, it might be assumed that BMI-1 has a similar role in cancer-initiating cells (CIC) in mEOC as in colorectal cancer (46). Likewise, as in colorectal carcinoma, the silencing of BMI-1 enhanced the therapeutic response to therapies containing platinum in ovarian carcinomas (47, 48). Kreso et al. identified the mechanism of action of the BMI1 inhibitor PTC-209, which inhibited the self-renewal of colorectal CICs (46). Recently PTC-028 inhibitor was established as an effective anti-cancer treatment for ovarian tumors, compared to standard cisplatin/paclitaxel (49). According to previous data focused on BMI-1 in epithelial tumor cells, an elevated expression in 80.9% of ovarian cancers and a link to tumor aggressiveness was shown (45), while platinum sensitivity of EOC cells was improved by knocking out BMI-1. Down-regulating BMI-1 enhanced the production of reactive oxygen species, promoted the DNA damage repair pathway, and promoted cisplatin-induced apoptosis (50). This is in line with our finding of a slightly better PFS for patients with negative or low BMI1 protein expression as measured by immunohistochemical staining.

To our knowledge, this is the first study to investigate BMI-1 expression and its correlation with conventional prognostic parameters as well as survival specifically associated with mOC. Previous studies have observed that BMI-1 expression is associated with worse clinical outcomes and poor prognostic markers in human cancers (51–55). However, there is little information regarding the prognostic value of BMI-1 expression with regard to clinical outcomes in patients diagnosed with mOC.

The expression levels of BMI-1 in mOC cell lines were compared to those in cell lines of high-grade serous origin by western blotting. BMI-1 expression levels were determined in all cell lines but varied in both groups. Furthermore, PCA analysis of gene expression profiles was conducted using the gene expression signatures from 14 ovarian cancer cell lines. Gene expression profiling showed that mucinous cell lines differentiated from the other HGSC cell lines, once more indicating its distinct entity.

In the present study, the protein expression of BMI-1 was investigated by IHC in mOC. There was no significant correlation between BMI-1 expression in mOC and FIGO, family history of gastric or colon cancer, LN status, or patient age. Although there was a trend for better PFS in BMI1low, we found no significant difference in BMI-1 expression in relation to PFS. Excluding cases with doubts about the primary complicates the inclusion of advanced tumor samples, therefore overall survival data could not be analyzed.

In silico and in vitro analyses revealed mOC to be a distinct entity, quite different from other histological epithelial types of ovarian cancer. To analyze these differences thoroughly would be beyond the scope of this study, regarding advancing therapeutic options (54, 56–58).

BMI-1 has a wide range of functions as it manages to regulate the cell cycle by controlling the tumor suppressor proteins p16INK4a and p14ARF, and plays an important role in tumor heterogeneity and relapse (22). Hence, further research to identify effective treatment approaches for patients with this molecular subtype of ovarian cancer is urgently required. Our study investigated the roles of BMI-1 in the development of mOC. To confirm BMI-1 as a potential therapeutic target, further studies should be performed to verify our hypothesis.

Acknowledgements

The Authors are thankful to their patients for participation in this study. The Authors would also like to especially thank the team at TOC lab.

Footnotes

  • ↵* These Authors contributed equally to this work.

  • Authors’ Contributions

    H. Kulbe, EI. Braicu, and S. Aboabker: designed research. S. Abobaker and H. Kulbe: performed the experiments. S. Aboabker, R. Richter and H. Kulbe: analyzed data. E. Taube: helped us with the immunohistochemistry experiments. EI. Braicu, H. Kulbe, E. Taube, S. Darb-Esfahani, C. Denkert, P. Jank, and J. Sehouli: helped with manuscript editing and generation of figures. S. Abobaker: wrote the paper.

  • Conflicts of Interest

    The Authors declare no conflicts of interest regarding this study.

  • Received January 26, 2022.
  • Revision received February 15, 2022.
  • Accepted February 18, 2022.

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Polycomb Protein BMI-1 as a Potential Therapeutic Target in Mucinous Ovarian Cancer
SALEM ABOBAKER, HAGEN KULBE, ELIANE T. TAUBE, SILVIA DARB-ESFAHANI, ROLF RICHTER, CARSTEN DENKERT, PAUL JANK, JALID SEHOULI, ELENA IOANA BRAICU
Anticancer Research Apr 2022, 42 (4) 1739-1747; DOI: 10.21873/anticanres.15650
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