p38β - MAPK11 and its role in female cancers

Abstract

Background: The p38MAPK family of Mitogen Activated Protein Kinases are a group of signalling molecules involved in cell growth, survival, proliferation and differentiation. The widely studied p38α isoform is ubiquitously expressed and is implicated in a number of cancer pathologies, as are p38γ and p38δ. However, the mechanistic role of the isoform, p38β, remains fairly elusive. Recent studies suggest a possible role of p38β in both breast and endometrial cancer with research suggesting involvement in bone metastasis and cancer cell survival. Female tissue specific cancers such as breast, endometrial, uterine and ovary account for over 3,000,000 cancer related incidents annually; advancements in therapeutics and treatment however require a deeper understanding of the molecular aetiology associated with these diseases. This study provides an overview of the MAPK signalling molecule p38β (MAPK11) in female cancers using an in-silico approach.

Methods: A detailed gene expression and methylation analysis was performed using datasets from cBioportal, CanSar and MEXPRESS. Breast, Uterine Endometrial, Cervical, Ovarian and Uterine Carcinosarcoma TCGA cancer datasets were used and analysed.

Results: Data using cBioportal and CanSAR suggest that expression of p38β is lower in cancers: BRCA, UCEC, UCS, CESC and OV compared to normal tissue. Methylation data from SMART and MEXPRESS indicate significant probe level variation of CpG island methylation status of the gene MAPK11. Analysis of the genes' two CpG islands shows that the gene was hypermethylated in the CpG1 with increased methylation seen in BRCA, CESC and UCEC cancer data sets with a slight increase of expression recorded in cancer samples. CpG2 exhibited hypomethylation with no significant difference between samples and high levels of expression. Further analysis from MEXPRESS revealed no significance between probe methylation and altered levels of expression. In addition, no difference in the expression of BRCA oestrogen/progesterone/HER2 status was seen.

Conclusion: This data provides an overview of the expression of p38β in female tissue specific cancers, showing a decrease in expression of the gene in BRCA, UCEC, CESC, UCS and OV, increasing the understanding of p38β MAPK expression and offering insight for future in-vitro investigation and therapeutic application.

Keywords: Breast cancer; Cbioportal; Cervical cancer; Female cancers; MAPK; MAPK11; Meexress; Methylation; Ovarian cancer; Pan-cancer; Smartapp; Uterine carcinosarcoma; canSar; p38β.

Fig. 1

a MAPK11 protein association network acquired by StringDB; b MAPK signalling pathways showing the initiation of JNK and p38 following external stimulation from UV and Reactive Oxygen Species (yellow) as well as CKs and growth factors (red). The p38 isoforms (green) are phosphorylated via MKK3/6 and MKK4 (grey) in response to ROS and environmental stress consequently increasing activation of downstream targets involved in processes such as cell migration, survival and differentiation, proliferation and apoptosis. UV: Ultraviolet radiation; ROS: Reactive Oxygen Species; GFs: Growth Factors; CKs: Cytokines; MEKK3,4: MAP3K3, MAP3K4; TAO: Serine/threonine-protein kinase Tao; ASK: Apoptosis signal-regulating kinase, MAP3K5; MLK1–3: Mitogen-Activated Protein Kinase Kinase Kinase 9–11; MKK4: Mitogen-Activated Protein Kinase Kinase 4; STAT1/3: Signal Transducer And Activator Of Transcription 1/3; ATF1,2: Activating Transcription Factor 1,2; cMYC: MYC Proto-Oncogene; ELK1: ETS Transcription Factor ELK1

Fig. 2

a PanCancer expression analyses of MAPK11 from canSAR database. A higher expression is seen in normal (blue) samples from female data sets: BRCA, OV, UCEC, and UCS compared with early (yellow) and advanced stage (pink) samples, with OV exhibiting the lowest level of expression in the advanced stage compared to all cancer data sets; b PanCancer data analysis using cBioPortal provides an overview of the landscape of MAPK11 genetic alterations across the range of TCGA data sets. OV, UCEC exhibit the highest level of alteration within the cancer types with deep deletion presenting as the most prevalent throughout the data sets. Of the female-specific cancers: BRCA, OV, CESC, UCEC, each exhibit varying levels of amplification specific alterations as well as high levels of deep deletion; c Deep deletions in BRCA 7/1084, CESC: 4/297, OV: 28/585, UCEC: 22/529 and UCS: 1/57. OV and the UCEC patients with deep deletions of MAPK11 are the biggest populations compared to all other cancers; d MAPK11 expression in female tissues: BRCA, CESC, UCEC, and UCS, indicating higher expression in normal tissue compared to downregulation in cancer data sets across all four cancer stages

Fig. 3

a Genomic information of the gene MAPK11. The segment plot showing the detailed information of genomic locations of CpGs of MAPK11, highlighting CpG island, shelves, and shores. The name and the type of each transcript are given. The coverage of the CpG islands is displayed as the red region. 14 probes are included in this genomic location with 10 of them to lie on the two island regions (CpG1 and CpG2); b Red bars on chromosome 22 indicate hypermethylated regions. MAPK11 gene can be found in the right end of the chromosome at the cytogenetic band 22q13.33 (green box)

Fig. 4

MAPK11 Methylation and correlation of expression with methylation in a BRCA; b CESC; c UCEC. In the top, the CpG1 island with 4 probes is showing a clear positive correlation of the expression of MAPK11 with the methylation status, while at the bottom, the CpG2 island with 6 probes, is showing a clear negative correlation of the expression with the methylation. Overall, a high methylation status has been observed in the first 4 positions targeted by the probes and lower methylation was observed in the following island, indicating that the gene is split into 2 genomic regions of different methylation status (see more at Additional files 1, 2 and 3)

Fig. 5

MEXPRESS view of the TCGA data for MAPK11 in breast invasive carcinoma. The samples are ordered by MAPK11 expression, revealing that the expression in the different stages is not significantly altered. Probes have been coloured differently depending on the genomic region they target. The detailed analysis for all cancers analysed can be found in Additional file 5