Type III TGF-β Receptor Down-Regulation Promoted Tumor Progression via Complement Component C5a Induction in Hepatocellular Carcinoma

SIMPLE SUMMARY: The clinical implications of TGFβR3 downregulation are currently unknown in hepatocellular carcinoma (HCC). Clinically, we identified that HCC patients with low expression levels of tumoral TGFβR3 exhibited significantly late tumor stages and shortened survival outcomes. Moreover, HCC patients developed lower plasma levels of TGFβR3 (sTGFβR3) (8.9 ng/mL) compared to healthy individuals (15.9 ng/mL), which represented a potential diagnostic marker. Similar to tumoral TGFβR3, low levels of plasma sTGFβR3 are also associated with poor clinical outcomes in HCC. To determine its tumor-suppressing capacities, continuous injection of sTGFβR3 in an orthotopic liver tumor model was performed, resulting in 2-fold tumor volume reduction compared to control. Decreased expression of TGFβR3 induced the upregulation of tumoral complement component C5a in HCC, which was found to contribute to poor clinical outcomes and promote tumor progression via a novel function in activating the tumor-promoting macrophages. ABSTRACT: Background and Aims—Transforming growth factor-beta (TGF-β) signaling orchestrates tumorigenesis and one of the family members, TGF-β receptor type III (TGFβR3), are distinctively under-expressed in numerous malignancies. Currently, the clinical impact of TGFβR3 down-regulation and the underlying mechanism remains unclear in hepatocellular carcinoma (HCC). Here, we aimed to identify the tumor-promoting roles of decreased TGFβR3 expression in HCC progression. Materials and Methods—For clinical analysis, plasma and liver specimens were collected from 100 HCC patients who underwent curative resection for the quantification of TGFβR3 by q-PCR and ELISA. To study the tumor-promoting mechanism of TGFβR3 downregulation, HCC mouse models and TGFβR3 knockout cell lines were applied. Results—Significant downregulation of TGFβR3 and its soluble form (sTGFβR3) were found in HCC tissues and plasma compared to healthy individuals (p < 0.01). Patients with <9.4 ng/mL sTGFβR3 exhibited advanced tumor stage, higher recurrence rate and shorter disease-free survival (p < 0.05). The tumor-suppressive function of sTGFβR3 was further revealed in an orthotopic mouse HCC model, resulting in 2-fold tumor volume reduction. In TGFβR3 knockout hepatocyte and HCC cells, increased complement component C5a was observed and strongly correlated with shorter survival and advanced tumor stage (p < 0.01). Interestingly, C5a activated the tumor-promoting Th-17 response in tumor associated macrophages. Conclusion—TGFβR3 suppressed tumor progression, and decreased expression resulted in poor prognosis in HCC patients through upregulation of tumor-promoting complement C5a.