Selective activation of TGFβ signaling by

Aberrant TGFβ 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) remains largely unknown. In this study, by using global transcriptomic analysis, we found that Porphyromonas gingivalis infection increased TGFβ secretion and promoted the activation of TGFβ/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 TGFβ/Smad signaling. Moreover, the increased GARP expression and the subsequent TGFβ activation was partially dependent on the fimbriae (FimA) of P. gingivalis. Intriguingly, eliminating P. gingivalis, inhibiting TGFβ, or silencing GARP led to a decreased phosphorylation of Smad2/3, the central mediator of TGFβ signaling, as well as an attenuated malignant phenotype of ESCC cells, indicating that the activation of TGFβ 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 TGFβ signaling and subsequently enhanced the tumor growth and lung metastasis. Collectively, our study indicated that TGFβ/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-TGFβ signaling could be a potential treatment strategy for patients with ESCC.