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TNK1 Induces Apoptosis by Regulating Bcl-2 Family Proteins in Immortalized Human Hepatocytes.

Record Type:	Electronic resources : Monograph/item
Title/Author:	TNK1 Induces Apoptosis by Regulating Bcl-2 Family Proteins in Immortalized Human Hepatocytes./
Author:	Huang, Jinyu.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2020,
Description:	93 p.
Notes:	Source: Masters Abstracts International, Volume: 82-10.
Contained By:	Masters Abstracts International82-10.
Subject:	Design. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28383922
ISBN:	9798708719027

TNK1 Induces Apoptosis by Regulating Bcl-2 Family Proteins in Immortalized Human Hepatocytes.
Huang, Jinyu.

TNK1 Induces Apoptosis by Regulating Bcl-2 Family Proteins in Immortalized Human Hepatocytes. - Ann Arbor : ProQuest Dissertations & Theses, 2020 - 93 p.

Source: Masters Abstracts International, Volume: 82-10.

Thesis (M.Sc.)--McGill University (Canada), 2020.

This item must not be sold to any third party vendors.

Primary liver cancer, with hepatocellular carcinoma (HCC) being the most common, is the second leading cause of cancer deaths worldwide. Liver cancer is one of the fastest rising types of cancer in North America and one with a poor prognosis. Any recovery from this disease is complicated by the fact that most patients have liver damage caused by the tumor, which limits its normal functions. Furthermore, liver cancers do not respond favorably to most currently available chemotherapeutic agents, thus reflecting an unmet need for new strategies to treat this deadly disease. Thirty-eight-negative kinase 1 (TNK1) is a member of the activated Cdc42-associated kinase (ACK) non-receptor tyrosine kinase family. The biological significance of TNK1 has never been fully characterized, but studies have demonstrated that TNK1 is a tumor suppressor involved in the negative regulation of cell growth. Accordingly, mice deficient for TNK1/KOS1 develop spontaneous tumors, including lymphomas and carcinomas at high rates. Furthermore, a high density single nucleotide polymorphism array and gene expression profilings revealed that 22% of newly diagnosed diffuse large B-cell lymphomas present an allelic loss and/or a downregulation of TNK1 expression, suggesting that it is also involved in human tumorigenesis. However, the role of TNK1 in HCC has not been studied. We thus set out to study the role of TNK1 in the regulation of cell growth and apoptosis in human hepatocyte cells.An immunohistochemistry assay of liver tissue samples from HCC patients revealed that the level of TNK1 expression is higher within normal tissue than that within HCC tissue. Consistent with the in vivo data, TNK1 expression was significantly higher in the human hepatocyte cell line than that in the HCC cell lines. Interestingly, overexpression of TNK1 induced apoptosis in IHH, PC-3, and HepG2 but not in p53 mutated Huh7 cells. Additionally, mitochondria isolation and Western blot assay demonstrated that TNK1 expression up-regulates Bak, down-regulates Bcl-xL and Mcl-1, causes release of cytochrome c from mitochondria into cytosol as well as cleavage of Caspase-9, indicating TNK1's involvement in the intrinsic pathway. Furthermore, by knocking down p53 with siRNA, we found that TNK1's ability to induce apoptosis is reduced and thus TNK1-induced apoptosis in IHH cells is p53-dependent. In conclusion, our study expands the knowledge of TNK1 as a tumor suppressor, reveals a novel mechanism of TNK1 inducing apoptosis, and highlights the therapeutic and preventive potential of TNK1 in HCC, providing insight on the development of novel anti-cancer drugs.

ISBN: 9798708719027Subjects--Topical Terms:

518875
Design.
Subjects--Index Terms:

TNK1

TNK1 Induces Apoptosis by Regulating Bcl-2 Family Proteins in Immortalized Human Hepatocytes.
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245 1 0 $a TNK1 Induces Apoptosis by Regulating Bcl-2 Family Proteins in Immortalized Human Hepatocytes.
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300 $a 93 p.
500 $a Source: Masters Abstracts International, Volume: 82-10.
500 $a Advisor: Lin, Rongtuan.
502 $a Thesis (M.Sc.)--McGill University (Canada), 2020.
506 $a This item must not be sold to any third party vendors.
520 $a Primary liver cancer, with hepatocellular carcinoma (HCC) being the most common, is the second leading cause of cancer deaths worldwide. Liver cancer is one of the fastest rising types of cancer in North America and one with a poor prognosis. Any recovery from this disease is complicated by the fact that most patients have liver damage caused by the tumor, which limits its normal functions. Furthermore, liver cancers do not respond favorably to most currently available chemotherapeutic agents, thus reflecting an unmet need for new strategies to treat this deadly disease. Thirty-eight-negative kinase 1 (TNK1) is a member of the activated Cdc42-associated kinase (ACK) non-receptor tyrosine kinase family. The biological significance of TNK1 has never been fully characterized, but studies have demonstrated that TNK1 is a tumor suppressor involved in the negative regulation of cell growth. Accordingly, mice deficient for TNK1/KOS1 develop spontaneous tumors, including lymphomas and carcinomas at high rates. Furthermore, a high density single nucleotide polymorphism array and gene expression profilings revealed that 22% of newly diagnosed diffuse large B-cell lymphomas present an allelic loss and/or a downregulation of TNK1 expression, suggesting that it is also involved in human tumorigenesis. However, the role of TNK1 in HCC has not been studied. We thus set out to study the role of TNK1 in the regulation of cell growth and apoptosis in human hepatocyte cells.An immunohistochemistry assay of liver tissue samples from HCC patients revealed that the level of TNK1 expression is higher within normal tissue than that within HCC tissue. Consistent with the in vivo data, TNK1 expression was significantly higher in the human hepatocyte cell line than that in the HCC cell lines. Interestingly, overexpression of TNK1 induced apoptosis in IHH, PC-3, and HepG2 but not in p53 mutated Huh7 cells. Additionally, mitochondria isolation and Western blot assay demonstrated that TNK1 expression up-regulates Bak, down-regulates Bcl-xL and Mcl-1, causes release of cytochrome c from mitochondria into cytosol as well as cleavage of Caspase-9, indicating TNK1's involvement in the intrinsic pathway. Furthermore, by knocking down p53 with siRNA, we found that TNK1's ability to induce apoptosis is reduced and thus TNK1-induced apoptosis in IHH cells is p53-dependent. In conclusion, our study expands the knowledge of TNK1 as a tumor suppressor, reveals a novel mechanism of TNK1 inducing apoptosis, and highlights the therapeutic and preventive potential of TNK1 in HCC, providing insight on the development of novel anti-cancer drugs.
520 $a Le carcinome hepatocellulaire (CHC), le plus frequent des cancers primitifs du foie, est la deuxieme cause de deces par cancer dans le monde. Le cancer du foie est l'un des types de cancer qui a un tres mauvais pronostic et a aussi la progression la plus rapide en Amerique du Nord. Toute guerison de cette maladie est compliquee par le fait que la plupart des patients presentent des lesions hepatiques causees par la tumeur, limitant ainsi les fonctions normales du foie. De plus, les cancers du foie ne repondent pas favorablement a la plupart des agents chimio-therapeutiques actuellement disponibles, refletant ainsi la necessite de trouver de nouvelles strategies pour traiter cette maladie mortelle. Thirty-eight-negative kinase 1 (TNK1) est un membre de la famille activated Cdc42-associated kinase (ACK) des tyrosines kinases non-recepteurs. L'impact biologique de TNK1 n'a jamais ete completement caracterise mais des etudes ont demontre que TNK1 est un suppresseur de tumeur implique dans la regulation negative de la croissance cellulaire. En consequence, les souris deficientes en TNK1 / KOS1 developpent des tumeurs spontanees, y compris des taux eleves de lymphomes et de carcinomes.En outre, une batterie a haute densite de polymorphismes d'un seul nucleotide ainsi que des profils d'expression genetique ont revele que 22% des lymphomes diffus a grandes cellules B nouvellement diagnostiques presentent une perte allelique et / ou une regulation negative de l'expression de TNK1, suggerant que ce dernier est egalement implique dans la tumorigenese chez l'humain. Cependant, le role de TNK1 dans le CHC n'a pas ete etudie. Nous avons donc entrepris d'etudier le role de TNK1 dans la regulation de la croissance cellulaire et de l'apoptose chez les hepatocytes humains.Le test d'immunohistochimie des tissus hepatiques de patients atteints de CHC a revele que le niveau d'expression de TNK1 est plus eleve dans le tissu normal que dans le tissu du CHC. Selon les donnees in vivo, l'expression de TNK1 etait significativement plus elevee dans la lignee cellulaire d'hepatocytes humains que dans les lignees cellulaires CHC. Il est interessant de noter que la surexpression de TNK1 a induit de l'apoptose dans les cellules IHH, PC-3 et HepG2, mais pas dans les Huh7-p53 mutantes. De plus, l'isolement des mitochondries et le Western blot ont demontre que l'expression de TNK1 augmente le niveau d'expression de Bak, et baisse celui de Bcl-xL et de Mcl-1, provoque la liberation du cytochrome c des mitochondries dans le cytosol ainsi que le clivage de la Caspase-9, indiquant l'implication de TNK1 dans la voie intrinseque.De plus, en faisant un knock down du p53 avec de l'ARNsi, nous avons constate que la capacite de TNK1 a induire l'apoptose est reduite et que l'apoptose induite par TNK1 dans les cellules IHH depend de p53.En conclusion, notre etude elargit les connaissances sur TNK1 en tant que suppresseur de tumeur. Elle revele aussi un nouveau mecanisme d'induction de l'apoptose par TNK1, de meme qu'elle met en evidence le potentiel therapeutique et preventif de TNK1 dans le CHC, offrant ainsi la possibilite de developpement de nouveaux medicaments anticancereux.
590 $a School code: 0781.
650 4 $a Design. $3 518875
650 4 $a Tumorigenesis. $3 3561727
650 4 $a Gene expression. $3 643979
650 4 $a Flow cytometry. $3 600581
650 4 $a Liver cancer. $3 3560852
650 4 $a Lymphoma. $3 802273
650 4 $a Cytochrome. $3 3683768
650 4 $a Cell growth. $3 3560747
650 4 $a Apoptosis. $3 600650
650 4 $a Kinases. $3 3558077
650 4 $a Cell culture. $3 604671
653 $a TNK1
653 $a Apoptosis
653 $a Bcl-2 family proteins
653 $a Immortalized human hepatocytes
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690 $a 0982
690 $a 0410
690 $a 0992
710 2 $a McGill University (Canada). $3 1018122
773 0 $t Masters Abstracts International $g 82-10.
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791 $a M.Sc.
792 $a 2020
793 $a English
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