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Article ; Online: Hepatobiliary Cancers: Progress in Diagnosis, Pathogenesis, and Treatment.

Pant, Kishor / Gradilone, Sergio A

Technology in cancer research & treatment

2022 Volume 21, Page(s) 15330338221097203

Abstract: Hepatobiliary cancers comprise a wide range of malignancies such as hepatocellular carcinoma and cholangiocarcinoma, and they are some of the most challenging to treat human neoplasms. Due to the rarity of the illnesses, the development of treatment ... ...

Abstract	Hepatobiliary cancers comprise a wide range of malignancies such as hepatocellular carcinoma and cholangiocarcinoma, and they are some of the most challenging to treat human neoplasms. Due to the rarity of the illnesses, the development of treatment measures for malignancies of the gastrointestinal system is far behind. The number of patients eligible for curative treatment is limited due to cancer's aggressive nature and the difficulties of early identification. Furthermore, surgery is frequently intrusive and linked with a significant level of risk. The therapy result of hepatobiliary cancers is unsatisfactory due to these complicated variables, leaving significant space for improvement.
MeSH term(s)	Bile Duct Neoplasms ; Bile Ducts, Intrahepatic ; Carcinoma, Hepatocellular/diagnosis ; Carcinoma, Hepatocellular/etiology ; Carcinoma, Hepatocellular/therapy ; Cholangiocarcinoma/diagnosis ; Cholangiocarcinoma/etiology ; Cholangiocarcinoma/therapy ; Humans ; Liver Neoplasms/diagnosis ; Liver Neoplasms/etiology ; Liver Neoplasms/therapy
Language	English
Publishing date	2022-05-11
Publishing country	United States
Document type	Editorial
ZDB-ID	2146365-7
ISSN	1533-0338 ; 1533-0346
ISSN (online)	1533-0338
ISSN	1533-0346
DOI	10.1177/15330338221097203
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Article ; Online: Cilia and Cancer: From Molecular Genetics to Therapeutic Strategies.

Carotenuto, Pietro / Gradilone, Sergio A / Franco, Brunella

Genes

2023 Volume 14, Issue 7

Abstract: Cilia are microtubule-based organelles that project from the cell surface with motility or sensory functions. Primary cilia work as antennae to sense and transduce extracellular signals. Cilia critically control proliferation by mediating cell-extrinsic ... ...

Abstract	Cilia are microtubule-based organelles that project from the cell surface with motility or sensory functions. Primary cilia work as antennae to sense and transduce extracellular signals. Cilia critically control proliferation by mediating cell-extrinsic signals and by regulating cell cycle entry. Recent studies have shown that primary cilia and their associated proteins also function in autophagy and genome stability, which are important players in oncogenesis. Abnormal functions of primary cilia may contribute to oncogenesis. Indeed, defective cilia can either promote or suppress cancers, depending on the cancer-initiating mutation, and the presence or absence of primary cilia is associated with specific cancer types. Together, these findings suggest that primary cilia play important, but distinct roles in different cancer types, opening up a completely new avenue of research to understand the biology and treatment of cancers. In this review, we discuss the roles of primary cilia in promoting or inhibiting oncogenesis based on the known or predicted functions of cilia and cilia-associated proteins in several key processes and related clinical implications.
MeSH term(s)	Humans ; Cilia/physiology ; Neoplasms/genetics ; Neoplasms/therapy ; Neoplasms/metabolism ; Cell Division ; Carcinogenesis/metabolism ; Molecular Biology
Language	English
Publishing date	2023-07-11
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2527218-4
ISSN	2073-4425 ; 2073-4425
ISSN (online)	2073-4425
ISSN	2073-4425
DOI	10.3390/genes14071428
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Article ; Online: Extracellular vesicles as therapeutic carriers of microRNAs for cholangiocarcinoma.

Gradilone, Sergio A

Hepatology (Baltimore, Md.)

2017 Volume 65, Issue 2, Page(s) 404–406

Language	English
Publishing date	2017-02
Publishing country	United States
Document type	Editorial
ZDB-ID	604603-4
ISSN	1527-3350 ; 0270-9139
ISSN (online)	1527-3350
ISSN	0270-9139
DOI	10.1002/hep.28925
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Article: Short-Chain Fatty Acid Butyrate Induces Cilia Formation and Potentiates the Effects of HDAC6 Inhibitors in Cholangiocarcinoma Cells.

Pant, Kishor / Richard, Seth / Gradilone, Sergio A

Frontiers in cell and developmental biology

2022 Volume 9, Page(s) 809382

Abstract: Cholangiocarcinoma (CCA) is a deadly form of liver cancer with limited therapeutic approaches. The pathogenesis of CCA involves the loss of primary cilia in cholangiocytes, an important organelle that regulates several key cellular functions including ... ...

Abstract	Cholangiocarcinoma (CCA) is a deadly form of liver cancer with limited therapeutic approaches. The pathogenesis of CCA involves the loss of primary cilia in cholangiocytes, an important organelle that regulates several key cellular functions including the regulation of cell polarity, growth, and differentiation, by a mechanism involving increased expression of deacetylases like HDAC6 and SIRT1. Therefore, cilia restoration may represent an alternative and novel therapeutic approach against CCA. Butyrate is produced by bacterial fermentation of fibers in the intestine and has been shown to inhibit SIRT1, showing antitumor effects on various cancers. Herein, we investigated the role of butyrate on CCA cell proliferation, migration, and EMT and evaluated the synergistic effects with specific HDAC6 inhibition. When CCA cells, including HuCCT1 and KMCH, were treated with butyrate, the cilia formation and acetylated-tubulin levels were increased, while no significant effects were observed in normal human cholangiocytes. Butyrate treatment also depicted reduced cell proliferation in HuCCT1 and KMCH cells, but on the other hand, it affected cell growth of the normal cholangiocytes only at high concentrations. In HuCCT1 cells, spheroid formation and cell migration were also halted by butyrate treatment. Furthermore, we found that butyrate augmented the previously described effects of HDAC6 inhibitors on CCA cell proliferation and migration by reducing the expression of CD44, cyclin D1, PCNA, Zeb1, and Vimentin. In summary, butyrate targets cancer cell growth and migration and enhances the anti-cancer effects of HDAC6 inhibitors in CCA cells, suggesting that butyrate may have therapeutic effects in CCA and other ciliopathies.
Language	English
Publishing date	2022-01-13
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2737824-X
ISSN	2296-634X
ISSN	2296-634X
DOI	10.3389/fcell.2021.809382
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Article ; Online: Cilia and Cancer: From Molecular Genetics to Therapeutic Strategies

Carotenuto, Pietro / Gradilone, Sergio A. / Franco, Brunella

Genes (Basel). 2023 July 11, v. 14, no. 7

2023

Abstract	Cilia are microtubule-based organelles that project from the cell surface with motility or sensory functions. Primary cilia work as antennae to sense and transduce extracellular signals. Cilia critically control proliferation by mediating cell-extrinsic signals and by regulating cell cycle entry. Recent studies have shown that primary cilia and their associated proteins also function in autophagy and genome stability, which are important players in oncogenesis. Abnormal functions of primary cilia may contribute to oncogenesis. Indeed, defective cilia can either promote or suppress cancers, depending on the cancer-initiating mutation, and the presence or absence of primary cilia is associated with specific cancer types. Together, these findings suggest that primary cilia play important, but distinct roles in different cancer types, opening up a completely new avenue of research to understand the biology and treatment of cancers. In this review, we discuss the roles of primary cilia in promoting or inhibiting oncogenesis based on the known or predicted functions of cilia and cilia-associated proteins in several key processes and related clinical implications.
Keywords	autophagy ; carcinogenesis ; cell cycle ; genome ; mutation ; organelles ; therapeutics
Language	English
Dates of publication	2023-0711
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article ; Online
ZDB-ID	2527218-4
ISSN	2073-4425
ISSN	2073-4425
DOI	10.3390/genes14071428
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: The Role of Gut Microbiome-Derived Short-Chain Fatty Acid Butyrate in Hepatobiliary Diseases.

Pant, Kishor / Venugopal, Senthil K / Lorenzo Pisarello, Maria J / Gradilone, Sergio A

The American journal of pathology

2023 Volume 193, Issue 10, Page(s) 1455–1467

Abstract: The short-chain fatty acid butyrate, produced from fermentable carbohydrates by gut microbiota in the colon, has multiple beneficial effects on human health. At the intestinal level, butyrate regulates metabolism, helps in the transepithelial transport ... ...

Abstract	The short-chain fatty acid butyrate, produced from fermentable carbohydrates by gut microbiota in the colon, has multiple beneficial effects on human health. At the intestinal level, butyrate regulates metabolism, helps in the transepithelial transport of fluids, inhibits inflammation, and induces the epithelial defense barrier. The liver receives a large amount of short-chain fatty acids via the blood flowing from the gut via the portal vein. Butyrate helps prevent nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, inflammation, cancer, and liver injuries. It ameliorates metabolic diseases, including insulin resistance and obesity, and plays a direct role in preventing fatty liver diseases. Butyrate has different mechanisms of action, including strong regulatory effects on the expression of many genes by inhibiting the histone deacetylases and modulating cellular metabolism. The present review highlights the wide range of beneficial therapeutic and unfavorable adverse effects of butyrate, with a high potential for clinically important uses in several liver diseases.
MeSH term(s)	Humans ; Butyrates/metabolism ; Gastrointestinal Microbiome ; Fatty Acids, Volatile/pharmacology ; Fatty Acids, Volatile/therapeutic use ; Inflammation/drug therapy ; Non-alcoholic Fatty Liver Disease/drug therapy
Chemical Substances	Butyrates ; Fatty Acids, Volatile
Language	English
Publishing date	2023-07-06
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2943-9
ISSN	1525-2191 ; 0002-9440
ISSN (online)	1525-2191
ISSN	0002-9440
DOI	10.1016/j.ajpath.2023.06.007
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Article ; Online: Short-Chain Fatty Acid Butyrate Induces Cilia Formation and Potentiates the Effects of HDAC6 Inhibitors in Cholangiocarcinoma Cells

Kishor Pant / Seth Richard / Sergio A. Gradilone

Frontiers in Cell and Developmental Biology, Vol

2022 Volume 9

Abstract	Cholangiocarcinoma (CCA) is a deadly form of liver cancer with limited therapeutic approaches. The pathogenesis of CCA involves the loss of primary cilia in cholangiocytes, an important organelle that regulates several key cellular functions including the regulation of cell polarity, growth, and differentiation, by a mechanism involving increased expression of deacetylases like HDAC6 and SIRT1. Therefore, cilia restoration may represent an alternative and novel therapeutic approach against CCA. Butyrate is produced by bacterial fermentation of fibers in the intestine and has been shown to inhibit SIRT1, showing antitumor effects on various cancers. Herein, we investigated the role of butyrate on CCA cell proliferation, migration, and EMT and evaluated the synergistic effects with specific HDAC6 inhibition. When CCA cells, including HuCCT1 and KMCH, were treated with butyrate, the cilia formation and acetylated-tubulin levels were increased, while no significant effects were observed in normal human cholangiocytes. Butyrate treatment also depicted reduced cell proliferation in HuCCT1 and KMCH cells, but on the other hand, it affected cell growth of the normal cholangiocytes only at high concentrations. In HuCCT1 cells, spheroid formation and cell migration were also halted by butyrate treatment. Furthermore, we found that butyrate augmented the previously described effects of HDAC6 inhibitors on CCA cell proliferation and migration by reducing the expression of CD44, cyclin D1, PCNA, Zeb1, and Vimentin. In summary, butyrate targets cancer cell growth and migration and enhances the anti-cancer effects of HDAC6 inhibitors in CCA cells, suggesting that butyrate may have therapeutic effects in CCA and other ciliopathies.
Keywords	short-chain fatty acid ; butyrate ; HDAC6 ; cilia ; cholangiocarcinoma ; Biology (General) ; QH301-705.5
Subject code	610
Language	English
Publishing date	2022-01-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Role of Histone Deacetylases in Carcinogenesis: Potential Role in Cholangiocarcinoma.

Pant, Kishor / Peixoto, Estanislao / Richard, Seth / Gradilone, Sergio A

Cells

2020 Volume 9, Issue 3

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Acetylation ; Biological Products/pharmacology ; Biological Products/therapeutic use ; Carcinogenesis/drug effects ; Carcinogenesis/pathology ; Cholangiocarcinoma/drug therapy ; Cholangiocarcinoma/enzymology ; Cholangiocarcinoma/pathology ; Histone Deacetylases/metabolism ; Humans ; Models, Biological
Chemical Substances	Biological Products ; Histone Deacetylases (EC 3.5.1.98)
Language	English
Publishing date	2020-03-23
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells9030780
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Article: Role of Glucose Metabolism Reprogramming in the Pathogenesis of Cholangiocarcinoma.

Pant, Kishor / Richard, Seth / Peixoto, Estanislao / Gradilone, Sergio A

Frontiers in medicine

2020 Volume 7, Page(s) 113

Abstract: Cholangiocarcinoma (CCA) is one of the most lethal cancers, and its rate of occurrence is increasing annually. The diagnoses of CCA patients remain elusive due to the lack of early symptoms and is misdiagnosed as HCC in a considerable percentage of ... ...

Abstract	Cholangiocarcinoma (CCA) is one of the most lethal cancers, and its rate of occurrence is increasing annually. The diagnoses of CCA patients remain elusive due to the lack of early symptoms and is misdiagnosed as HCC in a considerable percentage of patients. It is crucial to explore the underlying mechanisms of CCA carcinogenesis and development to find out specific biomarkers for early diagnosis of CCA and new promising therapeutic targets. In recent times, the reprogramming of tumor cells metabolism has been recognized as a hallmark of cancer. The modification from the oxidative phosphorylation metabolic pathway to the glycolysis pathway in CCA meets the demands of cancer cell proliferation and provides a favorable environment for tumor development. The alteration of metabolic programming in cancer cells is complex and may occur via mutations and epigenetic modifications within oncogenes, tumor suppressor genes, signaling pathways, and glycolytic enzymes. Herein we review the altered metabolism in cancer and the signaling pathways involved in this phenomena as they may affect CCA development. Understanding the regulatory pathways of glucose metabolism such as Akt/mTOR, HIF1α, and cMyc in CCA may further develop our knowledge of this devastating disease and may offer relevant information in the exploration of new diagnostic biomarkers and targeted therapeutic approaches for CCA.
Language	English
Publishing date	2020-04-03
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2775999-4
ISSN	2296-858X
ISSN	2296-858X
DOI	10.3389/fmed.2020.00113
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Article ; Online: Cholangiopathies and the noncoding revolution.

Gradilone, Sergio / Brunetti-Pierri, Nicola / Piccolo, Pasquale

Current opinion in gastroenterology

2022 Volume 38, Issue 2, Page(s) 128–135

Abstract: Purpose of review: Noncoding RNAs (ncRNAs), including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) among others, have attracted a great deal of attention for their potential role as master regulators of gene expression and as therapeutic targets. ...

Abstract	Purpose of review: Noncoding RNAs (ncRNAs), including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) among others, have attracted a great deal of attention for their potential role as master regulators of gene expression and as therapeutic targets. This review focuses on recent advances on the role of ncRNAs in the pathogenesis, diagnosis and treatment of diseases of the cholangiocytes (i.e. cholangiopathies). Recent findings: In the recent years, there has been an exponential growth in the knowledge on ncRNAs and their role in cholangiopathies, particularly cholangiocarcinoma. Summary: Although several studies focused on miRNAs as noninvasive biomarkers for diagnosis and staging, several studies also highlighted their functions and provided new insights into disease mechanisms.
MeSH term(s)	Bile Duct Neoplasms/diagnosis ; Bile Duct Neoplasms/genetics ; Bile Ducts, Intrahepatic/metabolism ; Cholangiocarcinoma/diagnosis ; Cholangiocarcinoma/genetics ; Humans ; MicroRNAs/genetics ; MicroRNAs/metabolism ; RNA, Long Noncoding/genetics ; RNA, Long Noncoding/metabolism
Chemical Substances	MicroRNAs ; RNA, Long Noncoding
Language	English
Publishing date	2022-02-23
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	632571-3
ISSN	1531-7056 ; 0267-1379
ISSN (online)	1531-7056
ISSN	0267-1379
DOI	10.1097/MOG.0000000000000806
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