CD109 identified in circulating proteomics mitigates postoperative recurrence in chronic rhinosinusitis with nasal polyps by suppressing TGF-β1-induced epithelial-mesenchymal transition.

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common inflammatory disorder with a high rate of recurrence. This study aimed to explore biomarkers for identifying patients with recurrent CRSwNP (rCRSwNP).

Methods: We recruited two independent cohorts. In the discovery cohort, rCRSwNP patients and non-recurrent CRSwNP (non-rCRSwNP) patients were recruited, and the serum proteomic profile was characterized. The top 5 upregulated and downregulated proteins were confirmed in the validation cohort by ELISA, WB, and qRT-PCR, and their predictive values for postoperative recurrence were assessed. In vitro, human nasal epithelial cells (HNEpCs) were employed to assess the ability of candidate proteins to induce epithelial-mesenchymal transition (EMT).

Results: Serum proteomics identified 53 different proteins, including 30 increased and 23 decreased, between the rCRSwNP and non-rCRSwNP groups. ELISA results revealed that serum levels of CD163 and TGF-β1 were elevated, CD109 and PRDX2 were decreased in the rCRSwNP group compared to the non-rCRSwNP group, and serum CD163, TGF-β1, and CD109 levels were proved to be associated with the risk of postoperative recurrence. In addition, qRT-PCR and WB revealed that tissue CD163, TGF-β1, and CD109 expressions in rCRSwNP patients were enhanced compared to those non-rCRSwNP patients. Kaplan-Meier analysis showed that increased CD163 and TGF-β1 expression and decreased CD109 expression are associated with the risk of recurrence in CRSwNP patients. Receiver operating characteristic curves showed that TGF-β1 and CD109 had superior diagnostic performances for rCRSwNP. In vitro experiments showed that TGF-β1 promoted EMT in HNEpCs, and overexpression of CD109 reversed this effect. Functional recovery experiments confirmed that CD109 could attenuate EMT in HNEpCs by inhibiting the TGF-β1/Smad signaling pathway, attenuating EMT in epithelial cells.

Conclusion: Our data suggested that TGF-β1 and CD109 might serve as promising predictors of rCRSwNP. The TGF-β1/Smad pathway was implicated in fostering EMT in epithelial cells, particularly those exhibiting low expression of CD109. Consequently, the absence of CD109 expression in epithelial cells could be a potential mechanism underlying rCRSwNP.