Selective activation of TGF signaling by P. gingivalis-mediated upregulation of GARP aggravates esophageal squamous cell carcinoma

Aberrant TGF13 signaling plays critical roles in the progression of multiple cancers; however, the functional mechanism of this signaling network in the infectious milieu of Esophageal Squamous Cell Carcinoma (ESCC) re-mains largely unknown. In this study, by using global transcriptomic analysis, we found that Porphyromonas gingiva-lis infection increased TGF13 secretion and promoted the activation of TGF13/Smad signaling in cultured cells and in clinical ESCC samples. Furthermore, we demonstrated for the first time that P. gingivalis enhanced the expression of Glycoprotein A repetitions predominant (GARP), thereby activating TGF13/Smad signaling. Moreover, the increased GARP expression and the subsequent TGF13 activation was partially dependent on the fimbriae (FimA) of P. gingiva-lis. Intriguingly, eliminating P. gingivalis, inhibiting TGF13, or silencing GARP led to a decreased phosphorylation of Smad2/3, the central mediator of TGF13 signaling, as well as an attenuated malignant phenotype of ESCC cells, indi-cating that the activation of TGF13 signaling could be an adverse prognostic factor of ESCC. Consistently, our clinical data demonstrated that the phosphorylation of Smad2/3 and the expression of GARP were positively correlated to the poor prognosis of ESCC patients. Lastly, using xenograft models, we found that P. gingivalis infection remarkably activated TGF13 signaling and subsequently enhanced the tumor growth and lung metastasis. Collectively, our study indicated that TGF13/Smad signaling mediates the oncogenic function of P. gingivalis in ESCC, which is augmented by the expression of GARP. Therefore, targeting either P. gingivalis or GARP-TGF13 signaling could be a potential treat-ment strategy for patients with ESCC.