The role of myoglobin in epithelial cancers: Insights from transcriptomics

The muscle-associated respiratory protein myoglobin (MB) is expressed in multiple types of cancer, including breast and prostate tumors. In Kaplan-Meier analyses of the two tumor types, MB positivity is associated with favorable prognoses. Despite its well-characterized function in myocytes, the role of MB in cancer remains unclear. To study the impact of endogenous MB expression, small interfering RNA MB-knockdown cells were engineered using breast, prostate and colon cancer cell lines (MDA-MB468, LNCaP, DLD-1), and their transcriptomes were investigated using RNA-Seq at different oxygen levels. In MB-positive cells, increased expression of glycolytic genes was observed, which was possibly…

The Different Immune Profiles of Normal Colonic Mucosa in Cancer-Free Lynch Syndrome Carriers and Lynch Syndrome Colorectal Cancer Patients.

ABSTRACT Background and aims Due to the high load of immunogenic frameshift neoantigens, tumors arising in individuals with Lynch syndrome (LS), the most common inherited colorectal cancer (CRC) syndrome, are characterized by a pronounced immune infiltration. However, the immune status of normal colorectal mucosa in LS is not well characterized. We assessed the immune infiltrate in tumor-distant normal colorectal mucosa from LS CRC patients, sporadic microsatellite-unstable (MSI) and microsatellite-stable (MSS) CRC patients, and cancer-free LS carriers. Methods CD3-positive, FOXP3-positive and CD8-positive T cells were quantified in 219, 233 and 201 formalin-fixed paraffin-embedded (FFPE) n…

[68Ga]Ga-DATA5m.SA.FAPi PET/CT: Specific Tracer-uptake in Focal Nodular Hyperplasia and potential Role in Liver Tumor Imaging.

Myoglobin, expressed in brown adipose tissue of mice, regulates the content and activity of mitochondria and lipid droplets

Abstract The identification of novel physiological regulators that stimulate energy expenditure through brown adipose tissue (BAT) activity in substrate catalysis is of utmost importance to understand and treat metabolic diseases. Myoglobin (MB), known to store or transport oxygen in heart and skeletal muscles, has recently been found to bind fatty acids with physiological constants in its oxygenated form (i.e., MBO2). Here, we investigated the in vivo effect of MB expression on BAT activity. In particular, we studied mitochondrial function and lipid metabolism as essential determinants of energy expenditure in this tissue. We show in a MB-null (MBko) mouse model that MB expression in BAT i…

Additional file 1: of Where is the limit of prostate cancer biomarker research? Systematic investigation of potential prognostic and diagnostic biomarkers

Supplementary Data. List of abbreviations. (PDF 29 kb)

Extensive transcriptional complexity during hypoxia-regulated expression of the myoglobin gene in cancer.

Recently, the ectopic expression of myoglobin (MB) was reported in human epithelial cancer cell lines and breast tumor tissues, where MB expression increased with hypoxia. The better prognosis of MB-positive breast cancer patients suggested that the globin exerts a tumor-suppressive role, possibly by impairing mitochondrial activity in hypoxic breast carcinoma cells. To better understand MB gene regulation in cancer, we systematically investigated the architecture of the human MB gene, its transcripts and promoters. In silico analysis of transcriptome data from normal human tissues and cancer cell lines, followed by RACE-PCR verification, revealed seven novel exons in the MB gene region, mo…

Fibroblast activation protein inhibitor (FAPi) positive tumour fraction on PET/CT correlates with Ki-67 in liver metastases of neuroendocrine tumours

Abstract Aim Gallium-68-labelled inhibitors of the fibroblast activation protein (FAPi) enable positron emission tomography/computed tomography (PET/CT) imaging of fibroblast activation. We evaluated if [68Ga]Ga-DATA5m.SA.FAPi PET/CT is related to Ki-67 as a marker of tumour aggressiveness in patients with liver metastases of NET. Methods Thirteen patients with liver metastases of a histologically confirmed NET who underwent PET/CT with [68Ga]Ga-DATA5m.SA.FAPi, [18F]FDG and [68Ga]Ga-DOTA-TOC were retrospectively analyzed. PET-positive liver tumour volumes were segmented for calculation of volume, SUVmax and PET-positive tumour fraction (TF). PET parameters were correlated with Ki-67. Result…

Ectopic myoglobin expression is associated with a favourable outcome in head and neck squamous cell carcinoma patients

BACKGROUND/AIM: Ectopic myoglobin (MB) expression, mediated by alternative and hypoxia-inducible transcription, has recently been demonstrated in several epithelial tumours. This study aimed to examine the expression of MB in hormone-independent head and neck squamous cell carcinomas (HNSCCs). PATIENTS AND METHODS: Using imunohistochemistry, ectopic MB expression was analyzed on tissue microarrays (TMAs) of 524 patients with localized and locally advanced primary and recurrent HNSCC who had undergone surgical treatment with curative intent. Associations of MB expression with survival and clinicopathological parameters were analyzed. RESULTS: MB expression was found in 45.8% of HNSCC patient…

Integrative clinical transcriptome analysis reveals TMPRSS2-ERG dependency of prognostic biomarkers in prostate adenocarcinoma.

In prostate adenocarcinoma (PCa), distinction between indolent and aggressive disease is challenging. Around 50% of PCa are characterized by TMPRSS2‐ERG (T2E)‐fusion oncoproteins defining two molecular subtypes (T2E‐positive/negative). However, current prognostic tests do not differ between both molecular subtypes, which might affect outcome prediction. To investigate gene‐signatures associated with metastasis in T2E‐positive and T2E‐negative PCa independently, we integrated tumor transcriptomes and clinicopathological data of two cohorts (total n = 783), and analyzed metastasis‐associated gene‐signatures regarding the T2E‐status. Here, we show that the prognostic value of biomarkers in PCa…

Endogenous Myoglobin in Breast Cancer Is Hypoxia-inducible by Alternative Transcription and Functions to Impair Mitochondrial Activity

Recently, immunohistochemical analysis of myoglobin (MB) in human breast cancer specimens has revealed a surprisingly widespread expression of MB in this nonmuscle context. The positive correlation with hypoxia-inducible factor 2α (HIF-2α) and carbonic anhydrase IX suggested that oxygen regulates myoglobin expression in breast carcinomas. Here, we report that MB mRNA and protein levels are robustly induced by prolonged hypoxia in breast cancer cell lines, in part via HIF-1/2-dependent transactivation. The hypoxia-induced MB mRNA originated from a novel alternative transcription start site 6 kb upstream of the ATG codon. MB regulation in normal and tumor tissue may thus be fundamentally diff…

Where is the limit of prostate cancer biomarker research? Systematic investigation of potential prognostic and diagnostic biomarkers

Background The identification of appropriate biomarkers is essential to support important clinical decisions in patients with prostate cancer. The aim of our study was a systematic bioinformatical analysis of the mRNA expression of all genes available for the prostate adenocarcinoma cohort of The Cancer Genome Atlas (TCGA), regarding their potential prognostic and diagnostic role. Methods The study cohort comprises 499 patients (TCGA prostate cancer cohort). mRNA expression data were available for approx. 20,000 genes. The bioinformatical statistical pipeline addressed gene expression differences in tumor vs. benign prostate tissue (including gene set enrichment analysis, GSEA) in samples f…

Additional file 7: of Where is the limit of prostate cancer biomarker research? Systematic investigation of potential prognostic and diagnostic biomarkers

Table S6 Top 50 genes with statistically significant and independent association with biochemical recurrence-free survival in multivariate Cox regression analysis (dichotomization using median) in patients with prostate cancer. Estimates of their perspectivity for further research are provided. (PDF 65 kb)

Old proteins - new locations: myoglobin, haemoglobin, neuroglobin and cytoglobin in solid tumours and cancer cells

Aim:  The unexpected identification of myoglobin (MB) in breast cancer prompted us to evaluate the clinico-pathological value of MB, haemoglobin (HB) and cytoglobin (CYGB) in human breast carcinoma cases. We further screened for the presence of neuroglobin (NGB) and CYGB in tumours of diverse origin, and assessed the O2-response of HB, MB and CYGB mRNAs in cancer cell lines, to better elicit the links between this ectopic globin expression and tumour hypoxia. Methods:  Breast tumours were analysed by immunohistochemistry for HB, MB and CYGB and correlated with clinico-pathological parameters. Screening for CYGB and NGB mRNA expression in tumour entities was performed by hybridization, quant…

Additional file 6: of Where is the limit of prostate cancer biomarker research? Systematic investigation of potential prognostic and diagnostic biomarkers

Table S5 Full results of the multivariate Cox regression analysis for single genes. (TXT 1949 kb)

Additional file 3: of Where is the limit of prostate cancer biomarker research? Systematic investigation of potential prognostic and diagnostic biomarkers

Table S2 Full results of Gene Set Enrichment Analysis (GSEA) for tumor vs normal tissue using Gene Ontology Biological Processes database. (TXT 131 kb)

Additional file 2: of Where is the limit of prostate cancer biomarker research? Systematic investigation of potential prognostic and diagnostic biomarkers

Table S1 Pairwise comparison of the gene expression of normal and tumor tissue using negative binomial generalized log-linear model and correction for false discovery rate (FDR). (TXT 2100 kb)

Additional file 5: of Where is the limit of prostate cancer biomarker research? Systematic investigation of potential prognostic and diagnostic biomarkers

Table S4 Correlation between ISUP histological grade group of the tumor (dichotomized as high-grade, ≥4 + 4, vs low-grade tumors) and mRNA expression of single genes. Correlation analysis for ISUP grade groups (Groups 1–5) is provided in parallel for comparison. Delta of Pearson r correlation levels is calculated for these 2 different settings. (TXT 2104 kb)

Additional file 4: of Where is the limit of prostate cancer biomarker research? Systematic investigation of potential prognostic and diagnostic biomarkers

Table S3 Correlation between ISUP histological grade group of the tumor (Grade groups 1â 5) and mRNA expression of single genes, univariate Cox-regression analysis with biochemical recurrence as an endpoint. Full list of genes (nâ =â 17,681). (TXT 3078 kb)

Additional file 8: of Where is the limit of prostate cancer biomarker research? Systematic investigation of potential prognostic and diagnostic biomarkers

Table S7 Results of the multivariate Cox regression analysis for single genes separately for patients of ISUP grade groups 2â 5. (TXT 1940 kb)