Background The miRNAs of the miR-200 family are critical regulators of oncogene and tumor suppressor genes. Preliminary data from a limited number of patients with SS-associated lymphoma suggested that the expression of miR200b-5p in MSGs may be downregulated in lymphoma.
Objectives To validate whether low miR200b-5p MSG-levels are associated with SS-related lymphomas and if they are deregulated before lymphoma development, suggesting a possible prognostic value.
Methods miR200b-5p expression was analyzed by quantitative real-time PCR in total RNA from MSG tissues obtained from 77 SS patients and 9 patients with non-SS sialadenitis associated with sarcoidosis, HCV infection (4 each) or HBV (1 that was also diagnosed with MALT lymphoma). with chronic sialadenitis associated with sarcoidosis, HCV (4-each) or HBV infection (1 who was also diagnosed with MALT-lymphoma). SS-patients included 28 that did not develop lymphoma during follow-up (without lymphoma; median follow-up time since biopsy performance, range: 6yrs, 1–12.75yrs), 18 that developed lymphoma in the future (prelymphoma; median follow-up time till lymphoma diagnosis, range: 3.59yrs, 0.42–8.5yrs, 15-MALT, 2-NMZL, 1-DLCBL) and 32 with SS-associated lymphoma at the time of biopsy (lymphoma; 25-MALT, 2-NMZL, 2-DLCBL, 1-BALT, 1-LP and 1-SLL). In 15 cases, we had sequential MSG-samples from prelymphoma patients who transitioned to lymphoma (12-MALT, 2-NMZL, 1-DLCBL).
Results Tukey's multiple comparison revealed that miR200b-5p levels were significantly down-regulated in MSG tissues of prelymphoma and lymphoma SS-patients (mean relative expression±SE: 0.37±0.10 and 0.26±0.06, respectively) compared to SS-patients without lymphoma (0.67±0.07; p≤0.05 and p≤0.0001 for pre- and lymphoma, respectively) or non-SS sialadenitis (0.85±0.28, p≤0.05 and p≤0.01, respectively). Interestingly, low miR200b-5p levels were detected in HBV patient that had MALT lymphoma (0.17). The expression of miR200b-5p was not found to differ between patients with SS without lymphoma and non-SS sialadenitis, or SS-associated pre-lymphoma and lymphoma. The analysis of the 15 cases of SS patients that had sequential samples before and on lymphoma diagnosis revealed that miR200b-5p levels do not significantly change over transition to lymphoma. The miR200b-5p expression levels were negatively correlated with the biopsy focus score (r:-0.6550, p<0.0001), whereas they were not associated with the site or the number of involved sites, the type or the stage of lymphoma.
Conclusions The significantly low levels of miR200b-5p in MSG tissues of patients with SS-associated prelymphomas and lymphomas suggest that miR200b-5p deregulation is implicated in SS-lymphomagenesis. The downregulation of miR200b-5p in prelymphoma samples and the lack of change over transition to lymphoma suggest that it can serve as a prognostic marker for future lymphoma development. The prognostic value of miR200b-5p in SS-associated lymphomas, the expressing cell types and affected molecular pathways are under investigation.
Acknowledgements Funded by the Hellenic College of Rheumatology
Disclosure of Interest None declared
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