Biology subjects

Chou, F.

Publications and source records attributed to Chou, F..

4 recordsLinked to original sources

bioRxiv2022

Targeting TR4-induced RCC cells-derived exosomally initiated signaling increases Sunitinib efficacy

Sunitinib is the first-line therapy for metastatic clear cell renal cell carcinoma (RCC) via suppressing neoangiogenesis and tumor growth. The detailed mechanisms, especially whether and how RCC cells can impact endothelial cells sensitivity to Sunitinib, remain unclear. Here, we found that TR4 was commonly upregulated in RCC tissue and relative to tumor angiogenesis. Tube formation and Mouse aortic ring assay showed that the overexpression or knockdown of TR4 in RCC cells enhanced or reduced the angiogenesis of endothelial cells and their resistance to Sunitinib in vitro. Mechanistically, We found that TR4 transcriptionally increase ADAM15 expression, as a consequence, exosomes carrying relatively large amounts of ADAM15 secreted from RCC cell resulted in activating the EGFR phosphorylation and reducing the efficacy of Sunitinib in endothelial cells. Targeting the TR4-induced renal cancers-derived exosomelly initiated signaling with a small molecular, CRM197, increases sunitinib efficacy in vitro and xenograft tumor models. Taken together, our findings indicate a novel function of TR4 in RCC blunted the efficacy of sunitinib via exosomal ADAM15-induced activation of EGFR signaling pathway in endothelial cells.

cancer biology↗

bioRxiv2020

Tolerogenic Dendritic Cells Shape a Transmissible Gut Microbiota that Protects from Metabolic Diseases

Excess of chronic contact between microbial motifs and intestinal immune cells are known to trigger a low-grade inflammation involved in many pathologies such as obesity and diabetes. The important skewing of intestinal adaptive immunity in the context of diet-induced obesity (DIO) is well described but how dendritic cells (DCs) participate to these changes is still poorly documented. To address this question, transgenic mice with enhanced DCs lifespan and immunogenicity (DChBcl-2 mice), are challenged with a high fat diet. Those mice display resistance to DIO and metabolic alterations. The DIO resistant phenotype is associated with healthier parameters of intestinal barrier function and lower intestinal inflammation. DChBcl-2 DIO-resistant mice demonstrate a particular increase in tolerogenic DC numbers and function which is associated with strong intestinal IgA, Th17 and T regulatory immune responses. Microbiota composition and function analyses reveal that the DChBcl-2 mice microbiota is characterized by a lower immunogenicity and an enhanced butyrate production. Cohousing experiments and fecal microbial transplantations are sufficient to transfer the DIO resistance status to WT mice demonstrating that maintenance of DCs tolerogenic ability sustains a microbiota able to drive DIO resistance. DCs tolerogenic function is revealed as a new potent target in metabolic diseases management.

immunology↗

bioRxiv2020

Androgen Receptor promotes renal cell carcinoma (RCC) vasculogenic mimicry (VM) via altering TWIST1 nonsense-mediated decay through lncRNA-TANAR

While the androgen receptor (AR) may influence the progression of clear cell renal cell carcinoma (ccRCC), its role to impact vasculogenic mimicry (VM) to alter the ccRCC progression and metastasis remains obscure. Here we demonstrated that elevated AR expression was positively correlated with tumor-originated vasculogenesis in ccRCC patients. Consistently, in vitro research revealed AR promoted VM formation in ccRCC cell lines via modulating lncRNA-TANAR/TWIST1 signals. Mechanism dissection showed that AR could increase lncRNA-TANAR (TANAR) expression through binding to the androgen response elements (AREs) located on its promoter region. Moreover, we found that TANAR could impede nonsense-mediated mRNA decay (NMD) of TWIST1 mRNA by direct interaction with TWIST1 5’UTR. A preclinical study using in vivo mouse model with orthotopic xenografts of ccRCC cells further confirmed the in vitro data. Together, these results illustrated that AR-mediated lnc-TANAR signals might play a crucial role in ccRCC VM formation and metastasis, and targeting this newly identified AR/lncRNA-TANAR/TWIST1 signaling may help in the development of a novel anti-angiogenesis therapy to better suppress the ccRCC progression.View Full Text

cancer biology↗

bioRxiv2019

Olaparib and Enzalutamide synergistically suppress HCC progression via the AR-mediated miR-146a-5p/BRCA1 signaling

Hepatocellular carcinoma (HCC) is one of most common malignant tumors worldwide, however, the treatment for advanced HCC remains unsatisfactory. Here we found that Olaparib, a FDA approved PARP inhibitor, could enhance the cytotoxicity in HCC cells with a lower BRCA1 expression, and suppressing the AR with either Enz or AR-shRNA could further increase the Olaparib sensitivity to better suppress the HCC cell growth via a synergistic mechanism that may involve suppressing the expression of BRCA1 and other DNA damage response (DDR) genes. Mechanism studies revealed that Enz/AR signaling might transcriptional regulting the miR-146a-5p expression via binding to the AREs on its 5 promoter region, which could then lead to suppress the homologous recombination-related BRCA1 expression via direct binding to its 3 UTR of mRNA. Preclinical study using an in vivo mouse model also proved that combined Enz plus Olaparib led to better suppression of the HCC progression. Together, these in vitro/in vivo data suggest that combining Enz and Olaparib may help in the development of a novel therapy to better suppress the HCC progression.

synthetic biology↗