Gut dysbiosis in cutaneous T-cell lymphoma is characterized by shifts in relative abundances of specific bacterial taxa and decreased diversity in more advanced disease.

BACKGROUND: Cutaneous T-cell lymphoma (CTCL) patients often suffer from recurrent skin infections and profound immune dysregulation in advanced disease. The gut microbiome has been recognized to influence cancers and cutaneous conditions; however, it has not yet been studied in CTCL. OBJECTIVES: To investigate the gut microbiome in patients with CTCL and in healthy controls. METHODS: A case-control study was conducted between January 2019 and November 2020 at Northwestern's busy multidisciplinary CTCL clinic (Chicago, Illinois, USA) utilizing 16S ribosomal RNA gene amplicon sequencing and bioinformatics analyses to characterize the microbiota present in fecal samples of CTCL patients (n = 38) and age-matched healthy controls (n = 13) from the same geographical region. RESULTS: Gut microbial α-diversity trended lower in patients with CTCL and was significantly lower in patients with advanced CTCL relative to controls (P = 0.015). No differences in ß-diversity were identified. Specific taxa were significantly reduced in patient samples; significance was determined using adjusted P-values (q-values) that accounted for a false discovery rate threshold of 0.05. Significantly reduced taxa in patient samples included the phylum Actinobacteria (q = 0.0002), classes Coriobacteriia (q = 0.002) and Actinobacteria (q = 0.03), order Coriobacteriales (q = 0.003), and genus Anaerotruncus (q = 0.01). The families Eggerthellaceae (q = 0.0007) and Lactobacillaceae (q = 0.02) were significantly reduced in patients with high skin disease burden. CONCLUSIONS: Gut dysbiosis can be seen in patients with CTCL compared to healthy controls and is pronounced in more advanced CTCL. The taxonomic shifts associated with CTCL are similar to those previously reported in atopic dermatitis and opposite those of psoriasis, suggesting microbial parallels to the immune profile and skin barrier differences between these conditions. These findings may suggest new microbial disease biomarkers and reveal a new angle for intervention.

Arylsulfatase B regulates versican expression by galectin-3 and AP-1 mediated transcriptional effects.

Arylsulfatase B (N-acetylgalactosamine-4-sulfatase; ARSB) removes 4-sulfate groups from chondroitin-4-sulfate (C4S) and dermatan sulfate and is required for their degradation. In human prostate stromal and epithelial cells, when ARSB was silenced, C4S, versican and versican promoter activity increased, and the galectin-3 that co-immunoprecipitated with C4S declined. Galectin-3 silencing inhibited the ARSB-silencing-induced increases in versican and versican promoter due to effects on the AP-1-binding site in the versican promoter. These findings demonstrate for the first time the transcriptional mechanism whereby ARSB can regulate expression of an extracellular matrix proteoglycan with C4S attachments. In addition, following ARSB silencing, C4S that co-immunoprecipitated with versican increased, whereas co-immunoprecipitated EGFR declined, total EGFR increased and exogenous EGF-induced cell proliferation increased, suggesting profound effects of ARSB on vital cell processes.

Arylsulfatase B (N-acetylgalactosamine-4-sulfatase): potential role as a biomarker in prostate cancer.

BACKGROUND: The enzyme arylsulfatase B (ARSB; N-acetylgalactosamine-4-sulfatase) degrades chondroitin-4-sulfate (C4S) and is reduced in malignant colonic and mammary tissues but has not previously been evaluated in prostate cancer. METHODS: ARSB immunostaining was performed on two tissue microarrays (TMAs) and analyzed by digital image analysis, generating ARSB H-scores for prevalence and intensity of epithelial, stromal and combined epithelial and stromal immunostaining. Also, paired malignant and normal prostate tissues were analyzed for ARSB activity, C4S, total sulfated glycosaminoglycans and versican content. The quantities of C4S and of the epidermal growth factor receptor (EGFR) that co-immunoprecipitated with versican were determined in the normal and malignant paired prostate tissues. RESULTS: Forty-four cases of prostate cancer were paired by age (± 5 years), race, Gleason score (in order) and pathological TNM (tumor, node, metastasis) score. The pairs differed by recurrence vs non-recurrence of elevated PSA at ≥ 4 years. When TMA cores were analyzed for ARSB H-score, 18 of the 22 pairs had lower ARSB H-scores in the recurrent member of the pair, whereas higher initial PSA values were associated with recurrence in only 65% of the paired cases. In a second TMA, Gleason scores 6 and 7 were associated with higher ARSB H-scores than Gleason scores 8 and 9 for stroma, epithelium and stroma and epithelium combined (P=0.052, P=0.015, P<0.0001, respectively) and were inversely correlated (r=-0.98, -0.97 and -0.99, respectively). In other paired normal and malignant prostate tissues, ARSB activity was significantly higher in the normal tissues, and C4S and versican values were lower (P<0.0001). C4S that co-immunoprecipitated with versican was greater in the malignant than in the normal tissue, whereas total EGFR that co-immunoprecipitated with versican was reduced. CONCLUSIONS: Study findings suggest that ARSB may be useful as a prognostic biomarker in prostate cancer and that the biological action of ARSB on chondroitin sulfate may impact upon versican's effects in the tumor microenvironment.