| Autor: |
Yeung OWH; Department of Surgery, HKU-SZH & The University of Hong Kong, Pokfulam, Hong Kong SAR, China., Qi X; Department of Surgery, HKU-SZH & The University of Hong Kong, Pokfulam, Hong Kong SAR, China., Pang L; Department of Surgery, HKU-SZH & The University of Hong Kong, Pokfulam, Hong Kong SAR, China., Liu H; Department of Surgery, HKU-SZH & The University of Hong Kong, Pokfulam, Hong Kong SAR, China., Ng KTP; Department of Surgery, HKU-SZH & The University of Hong Kong, Pokfulam, Hong Kong SAR, China., Liu J; Department of Surgery, HKU-SZH & The University of Hong Kong, Pokfulam, Hong Kong SAR, China., Lo CM; Department of Surgery, HKU-SZH & The University of Hong Kong, Pokfulam, Hong Kong SAR, China., Man K; Department of Surgery, HKU-SZH & The University of Hong Kong, Pokfulam, Hong Kong SAR, China. |
| Abstrakt: |
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. |
