Dataset Information

Angiotensin receptor blockers retard the progression and fibrosis via inhibiting the viability of ^AGTR1+ CAFs in intrahepatic cholangiocarcinoma.

ABSTRACT:

Background

Intrahepatic cholangiocarcinoma (iCCA) is a highly lethal malignancy characterized by massive fibrosis and has ineffective adjuvant therapies. Here, we demonstrate the potential of angiotensin receptor blockers (ARBs) in targeting iCCA.

Methods

Masson's trichrome staining was used to assess the effect of ARBs in iCCA specimens, CCK8 and gel contraction assays in vitro and in xenograft models in vivo. RNA-seq and ATAC-seq were used for mechanistic investigations.

Results

Patients with iCCA who were administered ARBs had a better prognosis and a lower proportion of tumour stroma, indicating alleviated fibrosis. The presence of AGTR1, the ARBs receptor, is associated with a poor prognosis of iCCA and is highly expressed in tumour tissues and cancer-associated fibroblasts (CAFs). The ARBs strongly attenuated the viability of ^AGTR1+ CAFs in vitro and retarded tumour progression and fibrosis in xenograft models of co-cultured CAFs and iCCA cells. Still, they did not have a significant effect on ^AGTR1- CAFs. Moreover, ARBs decreased the secretion of ^AGTR1+ CAF-derived MFAP5 via the Hippo pathway, weakened the interaction between CAFs and iCCA cells, and impaired the aggressiveness of iCCA cells by attenuating the activation of the Notch1 pathway in iCCA cells.

Conclusions

ARBs exhibit anti-fibrotic function by inhibiting the viability of ^AGTR1+ CAFs. These findings support using ARBs as a novel therapeutic option for targeting iCCA.

SUBMITTER: Li JH

PROVIDER: S-EPMC9975461 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Publications

Angiotensin receptor blockers retard the progression and fibrosis via inhibiting the viability of <sup>AGTR1+</sup> CAFs in intrahepatic cholangiocarcinoma.

Li Jian-Hui JH Wu Xiao X Ni Xuhao X Li Ya-Xiong YX Xu Long L Hao Xiao-Yi XY Zhao Wei W Zhu Xiao-Xu XX Yin Xiao-Yu XY

Clinical and translational medicine 20230301 3

<h4>Background</h4>Intrahepatic cholangiocarcinoma (iCCA) is a highly lethal malignancy characterized by massive fibrosis and has ineffective adjuvant therapies. Here, we demonstrate the potential of angiotensin receptor blockers (ARBs) in targeting iCCA.<h4>Methods</h4>Masson's trichrome staining was used to assess the effect of ARBs in iCCA specimens, CCK8 and gel contraction assays in vitro and in xenograft models in vivo. RNA-seq and ATAC-seq were used for mechanistic investigations.<h4>Resu ...[more]

PMID: 36855786

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Project description:Background: Intrahepatic cholangiocarcinoma (iCCA) is a highly malignant subtype of cholangiocarcinoma (CCA) with poor prognosis. In iCCA, the interplay between the stroma and tumor cells results in resistance to adjuvant chemotherapy. Increasing evidence indicates that miR-206 participates in tumor progression, but its role in iCCA is still unclear. The aim of this study was to identify dysregulated miR-206 expression in iCCA and to further explore the underlying mechanism. Methods: MiR-206 expression was proven to be downregulated in iCCA tissues by qPCR, and its correlation with clinical characteristics and prognosis was investigated. iCCA-derived cancer-associated fibroblast cells (CAFs) and normal fibroblast cells (NFs) were isolated and identified. MiR-206 was knocked in or down in CAFs and CCA cells, respectively, to explore the role of miR-206, and coculture of these treated CCAs and CAFs was conducted to explore the effects of miR-206 on their mutual promoting effects. Exosomes carrying miR-206 and an orthotopic mouse model were used to determine the inhibitory effects of miR-206 on iCCA deterioration in vivo. Results: We confirmed that miR-206 is a suppressor of iCCA. Overexpressing miR-206 in CCA cells inhibited cell proliferation, migration and invasion. When cocultured with CCA cells, NFs downregulated miR-206 expression, and NFs were susceptible to transforming into CAFs. Moreover, CAFs promoted CCA cell malignant behaviors and gemcitabine resistance. Overexpressing miR-206 in CAFs or CCA cells inhibited this mutual promoting effect. Additionally, when delivered by exosomes, miR-206 suppressed tumor deterioration. And combined with gemcitabine, this treatment resulted in a longer survival time. Conclusion: Our study explained that the interaction between CCA cells and CAFs promoted iCCA deterioration. As a suppressive factor, miR-206 inhibited aggressive characteristics and gemcitabine resistance by interfering with this mutual promoting effect. This research elucidated the molecular mechanism underlying the unfavorable chemotherapeutic response of patients with iCCA, which provided a promising target for iCCA treatment.

Project description:Intrahepatic cholangiocarcinoma (iCCA), the second most common primary liver cancer, has high mortality rates because of its limited treatment options and acquired resistance to chemotherapy. Sulforaphane (SFN), a naturally occurring organosulfur compound found in cruciferous vegetables, exhibits multiple therapeutic properties, such as histone deacetylase (HDAC) inhibition and anti-cancer effects. This study assessed the effects of the combination of SFN and gemcitabine (GEM) on human iCCA cell growth. HuCCT-1 and HuH28 cells, representing moderately differentiated and undifferentiated iCCA, respectively, were treated with SFN and/or GEM. SFN concentration dependently reduced total HDAC activity and promoted total histone H3 acetylation in both iCCA cell lines. SFN synergistically augmented the GEM-mediated attenuation of cell viability and proliferation by inducing G2/M cell cycle arrest and apoptosis in both cell lines, as indicated by the cleavage of caspase-3. SFN also inhibited cancer cell invasion and decreased the expression of pro-angiogenic markers (VEGFA, VEGFR2, HIF-1α, and eNOS) in both iCCA cell lines. Notably, SFN effectively inhibited the GEM-mediated induction of epithelial–mesenchymal transition (EMT). A xenograft assay demonstrated that SFN and GEM substantially attenuated human iCCA cell-derived tumor growth with decreased Ki67+ proliferative cells and increased TUNEL+ apoptotic cells. The anti-cancer effects of every single agent were markedly augmented by concomitant use. Consistent with the results of in vitro cell cycle analysis, G2/M arrest was indicated by increased p21 and p-Chk2 expression and decreased p-Cdc25C expression in the tumors of SFN- and GEM-treated mice. Moreover, treatment with SFN inhibited CD34-positive neovascularization with decreased VEGF expression and GEM-induced EMT in iCCA-derived xenografted tumors. In conclusion, these results suggest that combination therapy with SFN with GEM is a potential novel option for iCCA treatment.

Dataset Information

Angiotensin receptor blockers retard the progression and fibrosis via inhibiting the viability of ^AGTR1+ CAFs in intrahepatic cholangiocarcinoma.

Background

Methods

Results

Conclusions

Publications

Angiotensin receptor blockers retard the progression and fibrosis via inhibiting the viability of <sup>AGTR1+</sup> CAFs in intrahepatic cholangiocarcinoma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Angiotensin receptor blockers retard the progression and fibrosis via inhibiting the viability of AGTR1+ CAFs in intrahepatic cholangiocarcinoma.

Background

Methods

Results

Conclusions

Publications

Angiotensin receptor blockers retard the progression and fibrosis via inhibiting the viability of <sup>AGTR1+</sup> CAFs in intrahepatic cholangiocarcinoma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Angiotensin receptor blockers retard the progression and fibrosis via inhibiting the viability of ^AGTR1+ CAFs in intrahepatic cholangiocarcinoma.