A positive feedback loop between Periostin and TGFβ1 induces and maintains the stemness of hepatocellular carcinoma cells via AP-2α activation

Abstract

Background Liver cancer stem cells (LCSCs) play key roles in the metastasis, recurrence, and chemotherapeutic resistance of hepatocellular carcinoma (HCC). Our previous research showed that the POSTN gene is closely related to the malignant progression and poor prognosis of HCC. This study aimed to elucidate the role of POSTN in generating LCSCs and maintaining their stemness as well as the underlying mechanisms. Methods Human HCC tissues and matched adjacent normal tissues were obtained from 110 patients. Immunohistochemistry, western blotting (WB), and RT-PCR were performed to detect the expression of POSTN and stemness factors. The roles of transforming growth factor (TGF)-β1 and AP-2α in the POSTN-induced stemness transformation of HCC cells were explored in vitro and in vivo using LCSCs obtained by CD133+ cell sorting. Results The high expression of POSTN was correlated with the expression of various stemness factors, particularly CD133, in our HCC patient cohort and in TCGA and ICGC datasets. Knockdown of POSTN expression decreased the abilities of HCC cell lines to form tumours in xenograft mouse models. Knockdown of POSTN expression also suppressed cell viability and clone formation, invasion, and sphere formation abilities in vitro. Knockdown of AP-2α attenuated the generation of CD133+ LCSCs and their malignant behaviours, indicating that AP-2α was a critical factor that mediated the POSTN-induced stemness transformation and maintenance of HCC cells. The role of AP-2α was verified by using a specific αvβ3 antagonist, cilengitide, in vitro and in vivo. Activation of POSTN could release TGFβ1 from the extracellular matrix and initiated POSTN/TGFβ1 positive feedback signalling. Furthermore, we found that the combined use of cilengitide and lenvatinib suppressed the growth of HCC cells with high POSTN expression more effectively than the use of lenvatinib alone in the patient-derived xenograft (PDX) mouse model. Conclusions The POSTN/TGFβ1 positive feedback pathway regulates the expression of stemness factors and the malignant progression of HCC cells by regulating the transcriptional activation of AP-2α. This pathway may serve as a new target for targeted gene therapy in HCC.

Matricellular Protein Periostin Promotes Pericyte Migration in Fibrotic Airways

“…By highlighting periostin as a possible contributing factor to cell migration, this process may be targeted and arrested early on. With both TGF-β and periostin having a similar effect on pericyte migration in scratch assays, as shown in Figure 3 , this suggests that there is a relationship between TGF-β and periostin as previously described by several other groups ( 26 , 27 ).…”

TGF-beta signal transduction: biology, function and therapy for diseases

“…In addition, activation of POSTN releases TGF-β1 from the ECM and initiates the POSTN/TGF-β1 positive feedback loop. Cilengitide plus lenvatinib suppresses tumor cell growth in a hepatocellular carcinoma mouse model [ 312 ]. Generally, cilengitide, combined with paclitaxel, is well tolerated and has antitumor activity in patients with advanced solid tumors [ 313 ].…”

Integrated Analysis Reveals the Gut Microbial Metabolite TMAO Promotes Inflammatory Hepatocellular Carcinoma by Upregulating POSTN

“…We found that the proliferation and migratory capacity of Hepa1-6 cells were significantly decreased after knockdown of Postn . In addition, downregulation of POSTN reduced the tumor-forming ability of HCC cell lines in xenograft mouse models ( Chen et al, 2021 ). Moreover, POSTN mRNA expression positively correlated in tumor tissues, but not in non-tumor tissues ( Kongkavitoon et al, 2018 ).…”