Retinoid X receptor α enhances human cholangiocarcinoma growth through simultaneous activation of Wnt/β‐catenin and nuclear factor‐κB pathways

Huang, Gui‐Li; Zhang, Wei; Ren, Hong‐Yue; Shen, Xue‐Ying; Chen, Qing‐Xi; Shen, Dong‐Yan

doi:10.1111/cas.12802

Cited by 23 publications

(23 citation statements)

References 33 publications

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“…These data are consistent with previous reports indicating the potential tumor suppressor capacity of SOX17 [8–11]. The Wnt/β-catenin pathway is very relevant in the promotion of cholangiocarcinogenesis [21, 22]. Wnt ligands are highly present in the tumor microenvironment and are released by both cancer-associated fibroblasts (CAFs) and activated macrophages [23].…”

Section: Discussionsupporting

confidence: 91%

SOX17 regulates cholangiocyte differentiation and acts as a tumor suppressor in cholangiocarcinoma

Merino-Azpitarte

Lozano

Perugorria

et al. 2017

Journal of Hepatology

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Background & aims Cholangiocarcinoma (CCA) is a biliary malignancy linked to genetic and epigenetic abnormalities, such as hypermethylation of SOX17 promoter. Here, the role of SOX17 in cholangiocyte differentiation and cholangiocarcinogenesis was studied. Methods SOX17 expression/function was evaluated along the differentiation of human induced pluripotent stem cells (iPSC) into cholangiocytes, in the dedifferentiation process of normal human cholangiocytes (NHC) in culture and in cholangiocarcinogenesis. Lentiviruses for SOX17 overexpression or knock-down were used. Gene expression and DNA methylation profiling were performed. Results SOX17 expression is induced in the last stage of cholangiocyte differentiation from iPSC and regulates the acquisition of biliary markers. SOX17 becomes downregulated in NHC undergoing dedifferentiation; experimental SOX17 knock-down in differentiated NHC downregulated biliary markers and promoted baseline and Wnt-dependent proliferation. SOX17 expression is lower in human CCA than in healthy tissue, which correlates with worse survival after tumor resection. In CCA cells, SOX17 overexpression decreased their tumorigenic capacity in murine xenograft models, which was related to increased oxidative stress and apoptosis. In contrast, SOX17 overexpression in NHC did not affect their survival but inhibited their baseline proliferation. In CCA cells, SOX17 inhibited migration, anchorage-independent growth and Wnt/β-catenin-dependent proliferation, and restored the expression of biliary markers and primary cilium length. In human CCA, SOX17 promoter was found hypermethylated and its expression inversely correlates with the methylation grade. In NHC, Wnt3a decreased SOX17 expression in a DNMT-dependent manner, whereas in CCA, DNMT1 inhibition or silencing upregulated SOX17. Conclusions SOX17 regulates the differentiation and maintenance of the biliary phenotype and functions as a tumor suppressor for CCA, being a potential prognostic marker and a promising therapeutic target.

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Section: Discussionsupporting

confidence: 91%

SOX17 regulates cholangiocyte differentiation and acts as a tumor suppressor in cholangiocarcinoma

Merino-Azpitarte

Lozano

Perugorria

et al. 2017

Journal of Hepatology

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“…This signaling pathway supports the published reports showing that calcium regulates ROS generation (Gorlach et al, 2015). Interestingly, RXRA knockdown was found to decrease cyclin D1 and PCNA expression (Huang et al, 2015), which could also contribute to the induction of cellular senescence.…”

Section: Discussionmentioning

confidence: 99%

The nuclear receptor RXRA controls cellular senescence by regulating calcium signaling

Warnier

Raynard

et al. 2018

Aging Cell

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Calcium signaling is emerging as a key pathway controlling cellular senescence, a stable cell proliferation arrest playing a fundamental role in pathophysiological conditions, such as embryonic development, wound healing, cancer, and aging. However, how calcium signaling is regulated is still only partially understood. The inositol 1, 4, 5‐trisphosphate receptor type 2 (ITPR2), an endoplasmic reticulum calcium release channel, was recently shown to critically contribute to the implementation of senescence, but how ITPR2 expression is controlled is unclear. To gain insights into the regulation of ITPR2 expression, we performed an siRNA screen targeting 160 transcription factors and epigenetic regulators. Interestingly, we discovered that the retinoid X receptor alpha (RXRA), which belongs to the nuclear receptor family, represses ITPR2 expression and regulates calcium signaling though ITPR2 and the mitochondrial calcium uniporter (MCU). Knockdown of RXRA induces the production of reactive oxygen species (ROS) and DNA damage via the ITPR2‐MCU calcium signaling axis and consequently triggers cellular senescence by activating p53, whereas RXRA overexpression decreases DNA damage accumulation and then delays replicative senescence. Altogether, our work sheds light on a novel mechanism controlling calcium signaling and cellular senescence and provides new insights into the role of nuclear receptors.

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“…IHC was performed as described previously [28]. Briefly, after antigen retrieval using pressure cooker boiling for 2 min, paraffine-embedded human CRC tissue sections were washed and incubated with anti-RARα antibody (1:200) overnight at 4°C followed by incubation with corresponding secondary antibody for 1 h. After washing, the slides were detected with the EliVision Plus Kit (Maixin Bio, Fuzhou, China) according to the manufacturer's instructions and then co-stained with hematoxylin to visualize nuclei.…”

Section: Immunohistochemistry (Ihc)mentioning

confidence: 99%

Oncogenic retinoic acid receptor α promotes human colorectal cancer growth through simultaneously regulating p21 transcription and GSK3β/β-catenin signaling

et al. 2017

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Retinoic acid receptor α (RARα) plays important roles in the progression of several cancers such as leukemia, breast cancer, and lung cancer. In this study, we demonstrated that RARα protein was frequently overexpressed in human CRC specimens and CRC cell lines. RARα knockdown decreased cell survival, proliferation, and colony formation in vitro and tumorigenic potential in nude mice. Specifically, RARα knockdown inhibited cell cycle progression at G1 phase through upregulation of cell cycle inhibitor p21, and downregulation of cyclinD1. Furthermore, RARα was directly recruited to the p21 promoter to inhibit the expression of p21. Simultaneously, RARα contributed to the progression of CRC cells in part due to upregulation of cyclinD1 via activation of GSK3β/β-catenin pathway. Molecular mechanism studies revealed RARα interacted with GSK3β and led to decreased expression of GSK3β at ser9, followed by increased β-catenin expression. Taken together, our results signified the importance of RARα in CRC and demonstrated that RARα promotes CRC progression through suppressing p21 transcription and enhancing GSK3β/β-catenin signaling. RARα might become a potential molecular target for the treatment of CRC.

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Retinoid X receptor α enhances human cholangiocarcinoma growth through simultaneous activation of Wnt/β‐catenin and nuclear factor‐κB pathways

Cited by 23 publications

References 33 publications

SOX17 regulates cholangiocyte differentiation and acts as a tumor suppressor in cholangiocarcinoma

SOX17 regulates cholangiocyte differentiation and acts as a tumor suppressor in cholangiocarcinoma

The nuclear receptor RXRA controls cellular senescence by regulating calcium signaling

Oncogenic retinoic acid receptor α promotes human colorectal cancer growth through simultaneously regulating p21 transcription and GSK3β/β-catenin signaling

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