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The multi-functional roles of mucin ...

Chen, Shih-Hsun.

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The multi-functional roles of mucin 16 and matrix metalloproteinases in cancer metastatis.

紀錄類型:	書目-語言資料,印刷品 : Monograph/item
正題名/作者:	The multi-functional roles of mucin 16 and matrix metalloproteinases in cancer metastatis./
作者:	Chen, Shih-Hsun.
面頁冊數:	164 p.
附註:	Source: Dissertation Abstracts International, Volume: 74-11(E), Section: B.
Contained By:	Dissertation Abstracts International74-11B(E).
標題:	Engineering, Biomedical. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3572758
ISBN:	9781303395239

The multi-functional roles of mucin 16 and matrix metalloproteinases in cancer metastatis.
Chen, Shih-Hsun.

The multi-functional roles of mucin 16 and matrix metalloproteinases in cancer metastatis. - 164 p.

Source: Dissertation Abstracts International, Volume: 74-11(E), Section: B.

Thesis (Ph.D.)--The Johns Hopkins University, 2013.

Metastasis, the leading cause of cancerous death, is a multistep process in which tumor cells shed from the primary tumor and enter the vascular system, where they interact extensively with host cells and followed by lodging in the distinct organs and forming colonies. During this process, adhesion of circulating tumor cells to the vasculature as well as cell invasion and migration toward the secondary organ are dominant factors for further metastatic spread.

ISBN: 9781303395239Subjects--Topical Terms:

1017684
Engineering, Biomedical.

The multi-functional roles of mucin 16 and matrix metalloproteinases in cancer metastatis.
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245 1 4 $a The multi-functional roles of mucin 16 and matrix metalloproteinases in cancer metastatis.
300 $a 164 p.
500 $a Source: Dissertation Abstracts International, Volume: 74-11(E), Section: B.
500 $a Adviser: Konstantinos Konstantopoulos.
502 $a Thesis (Ph.D.)--The Johns Hopkins University, 2013.
520 $a Metastasis, the leading cause of cancerous death, is a multistep process in which tumor cells shed from the primary tumor and enter the vascular system, where they interact extensively with host cells and followed by lodging in the distinct organs and forming colonies. During this process, adhesion of circulating tumor cells to the vasculature as well as cell invasion and migration toward the secondary organ are dominant factors for further metastatic spread.
520 $a Selectin facilitates metastasis by mediating specific interactions between selectin ligands on tumor cells and selectin-expressing host cells in the microvasculature. To date, the selectin ligands have yet to be identified on pancreatic cancer (PC), which has the lowest survival rate among cancers due to its propensity for early local invasion and metastasis. In the present study, using flow-based adhesion assays and biochemical techniques we discovered the membrane glycoprotein cancer antigen 125/mucin 16 (CA125/MUC16) as a functional E- and L-selectin ligand on PC cells under physiological fluid flow. The specific biochemical nature of this binding interaction is attributed to sialofucosylated structures displayed on both 0- and N-linked glycans of MUC16. These observations provide the connection between MUC16 overexpression in PC and metastatic risk.
520 $a In addition to the role as selectin ligands, MUC16 has been shown to be co-localized with mesothelin (MSLN), a cancer marker, at invading edges of pancreatic tumor tissues and correlated with poor survival rate, however, the role of MUC16-MSLN interaction in this invasion process has yet to be elucidated. With molecular biology approaches and cell-based assays, we herein explored the underlying molecular mechanism that the binding of MSLN to MUC16 on metastatic PC cells selectively induces matrix metalloproteinase-7 (MMP-7), which was strongly detected in pancreatic tumor tissue in the immunohistochemical analysis. Furthermore, MSLN-MUC16 interaction markedly enhanced PC cell invasion and motility via MMP-7 activation through p38 MAPK-dependent pathways using time-lapse micro-channel devices and transwell chemotaxis assays. These findings provide novel perspective on the enhanced metastatic potential associated with MSLN and MUC16 co-overexpression and the mechanism underlying MMP-7 activation in PC invasion.
520 $a Shear force not only mediates of selectin-ligand interaction but also stimulates tumor cell responses including the alterations of morphology and intracellular signaling cascades. We thus investigated the roles of flow-induced shear stress in the regulation of tumor cell metastatic potential and its underlying molecular mechanisms. Using chondrosarcoma cell lines as a model system, we demonstrated that low fluid shear exposure remarkably induced MMP-12 activity. In addition, the shear stress induces the rapid synthesis of IGF-2, VEGF-B, and VEGF-D, which in turn transactivates MMP-12 expression via PI3K and p38 MAPK-dependent pathways, leading to the enhanced invasive and migratory capabilities of chondrosarcoma cells. Those findings provide insights into the mechanism by which shear stress induces tumor cell metastatic potential and demonstrate the importance of mechanical environments in modulating molecular signaling, gene expression and functions in tumor cells.
520 $a Cumulatively, our data implicate the molecular functions of MUC16, MSLN, MMP-7, and MMP-12 in multiple steps of cancer metastasis. The roles of these oncogenic proteins in adhesion, migration, invasion, and signaling are pivotal in determining their ultimate effect on metastasis. In addition to the identification of MUC16 and MSLN as therapeutic targets, this work provides novel perspective of the mechanism underlying MMP-7 and MMP-12 activation in early local invasion and metastasis.
590 $a School code: 0098.
650 4 $a Engineering, Biomedical. $3 1017684
650 4 $a Health Sciences, Oncology. $3 1018566
650 4 $a Biology, Cell. $3 1017686
650 4 $a Biology, Molecular. $3 1017719
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710 2 $a The Johns Hopkins University. $b Chemical and Biomolecular Engineering. $3 2099945
773 0 $t Dissertation Abstracts International $g 74-11B(E).
790 $a 0098
791 $a Ph.D.
792 $a 2013
793 $a English
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3572758