Primary Cilia in Tumor Biology: The Primary Cilium as a Therapeutic Target in Cholangiocarcinoma

Gradilone, Sergio A.; Pisarello, María J. Lorenzo; LaRusso, Nicholas F.

doi:10.2174/1389450116666150223162737

Cited by 34 publications

(38 citation statements)

References 67 publications

(73 reference statements)

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“…Mature cholangiocytes have a single primary cilium extending from the apical membrane [26], which in addition to other physiological roles, functions as a structural cell cycle checkpoint. Thus, its loss or shortening induces proliferation in several cholangiopathies [26].…”

Section: Discussionmentioning

confidence: 99%

“…Thus, its loss or shortening induces proliferation in several cholangiopathies [26]. Human CCA cells show loss or decreased primary cilium length, which is dependent on the overexpression of HDAC6 that de-acetylates the cilium scaffold protein α-tubulin [19, 26]. SOX17 overexpression induced the downregulation of HDAC6 together with the restoration of primary cilium structure and size, indicating improved cell polarity and differentiation.…”

Section: Discussionmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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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“…The primary cilium is a sensory organelle expressed in almost every cell of the body, including cholangiocytes [58,59]. Several studies have reported that primary cilia can serve as antennae, which have mechanical and chemical sensory capabilities to communicate with the extracellular environment.…”

Section: Ciliary Assemblymentioning

confidence: 99%

“…Disorders linked with genetic mutations in ciliary proteins often lead to abnormality in cilia formation. Ciliary dysfunction has been associated with intellectual disabilities, Bardet-Biedl syndrome, polycystic kidney disease, obesity, oral facial syndrome, cancer, and others [58,60,61]. Specifically, decreased or distorted primary cilia in cholangiocytes have important clinical implications and are associated with many biliary diseases, including CCA [62,63].…”

Section: Ciliary Assemblymentioning

confidence: 99%

Role of Histone Deacetylases in Carcinogenesis: Potential Role in Cholangiocarcinoma

Pant

Peixoto

Richard

et al. 2020

Cells

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Cholangiocarcinoma (CCA) is a highly invasive and metastatic form of carcinoma with bleak prognosis due to limited therapies, frequent relapse, and chemotherapy resistance. There is an urgent need to identify the molecular regulators of CCA in order to develop novel therapeutics and advance diseases diagnosis. Many cellular proteins including histones may undergo a series of enzyme-mediated post-translational modifications including acetylation, methylation, phosphorylation, sumoylation, and crotonylation. Histone deacetylases (HDACs) play an important role in regulating epigenetic maintenance and modifications of their targets, which in turn exert critical impacts on chromatin structure, gene expression, and stability of proteins. As such, HDACs constitute a group of potential therapeutic targets for CCA. The aim of this review was to summarize the role that HDACs perform in regulating epigenetic changes, tumor development, and their potential as therapeutic targets for CCA.

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“…many new signaling pathways related to the primary cilium have been identified, and novel functions of the primary cilium, such as responding to microgravity, electromagnetic fields, nitric oxide and mediating carcinogenesis, have been confirmed, greatly augmenting the importance of the primary cilium (Gradilone, Pisarello, & LaRusso, 2017;Moser et al, 2013;Saternos & Aboualaiwi, 2018;Shi, Xie, et al, 2017;Yan et al, 2015). Here, we summarize our current understanding of new discoveries about the functional role of the primary cilium and novel insight into cellular signaling by the primary cilium in bone disease and cancer.…”

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confidence: 99%

Novel functions of the primary cilium in bone disease and cancer

Shi

Zhang

et al. 2019

Cytoskeleton

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The primary cilium, a sensory organelle that emanates from the cell surface of most mammalian cell types during growth arrest, has attracted the attention of many researchers over the past decade. Recently, a large number of new findings have assigned novel functions and roles to the primary cilium in signal transduction and related diseases, which has greatly augmented the importance of the cilium in human health and development. Here, we review emerging evidence supporting the primary cilium as a sensory organelle in signal transduction in microgravity, electromagnetic field sensing, chemosensation and tumorigenesis. We also present an overview of signal transduction crosstalk associated with the primary cilium in bone disease and cancer, including primary cilium-related Ca 2+ signaling, parathyroid hormone signaling, cAMP signaling, BMP/Smad1/5/8 signaling and Wnt signaling. We anticipate that emerging discoveries about the function of the primary cilium will provide novel insight into the molecular mechanisms of stimulus sensation, signal transduction and pathogenesis. K E Y W O R D Sbone disease, cancer, cytoskeleton, primary cilium, signal transduction

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Primary Cilia in Tumor Biology: The Primary Cilium as a Therapeutic Target in Cholangiocarcinoma

Cited by 34 publications

References 67 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

Role of Histone Deacetylases in Carcinogenesis: Potential Role in Cholangiocarcinoma

Novel functions of the primary cilium in bone disease and cancer

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