Expression of the Carboxy-Terminal Portion of MUC16/CA125 Induces Transformation and Tumor Invasion

The CA125 antigen is found in the serum of many patients with serous ovarian cancer and has been widely used as a disease marker. CA125 has been shown to be an independent factor for clinical outcome in this disease. In The Cancer Genome Atlas ovarian cancer project, MUC16 expression levels are freq...

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Main Authors:	Rao, Thapi D., Tian, Huasong, Ma, Xun, Yan, Xiujun, Thapi, Sahityasri, Schultz, Nikolaus, Rosales, Nestor, Monette, Sebastien, Wang, Amy, Hyman, David M., Levine, Douglas A., Solit, David, Spriggs, David R.
Format:	Online
Language:	English
Published:	Public Library of Science 2015
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4429113/

id	pubmed-4429113
recordtype	oai_dc
spelling	pubmed-44291132015-05-21 Expression of the Carboxy-Terminal Portion of MUC16/CA125 Induces Transformation and Tumor Invasion Rao, Thapi D. Tian, Huasong Ma, Xun Yan, Xiujun Thapi, Sahityasri Schultz, Nikolaus Rosales, Nestor Monette, Sebastien Wang, Amy Hyman, David M. Levine, Douglas A. Solit, David Spriggs, David R. Research Article The CA125 antigen is found in the serum of many patients with serous ovarian cancer and has been widely used as a disease marker. CA125 has been shown to be an independent factor for clinical outcome in this disease. In The Cancer Genome Atlas ovarian cancer project, MUC16 expression levels are frequently increased, and the highest levels of MUC16 expression are linked to a significantly worse survival. To examine the biologic effect of the proximal portion of MUC16/CA125, NIH/3T3 (3T3) fibroblast cell lines were stably transfected with the carboxy elements of MUC16. As few as 114 amino acids from the carboxy-terminal portion of MUC16 were sufficient to increase soft agar growth, promote matrigel invasion, and increase the rate of tumor growth in athymic nude mice. Transformation with carboxy elements of MUC16 was associated with activation of the AKT and ERK pathways. MUC16 transformation was associated with up-regulation of a number of metastases and invasion gene transcripts, including IL-1β, MMP2, and MMP9. All observed oncogenic changes were exclusively dependent on the extracellular “ectodomain” of MUC16. The biologic impact of MUC16 was also explored through the creation of a transgenic mouse model expressing 354 amino acids of the carboxy-terminal portion of MUC16 (MUC16c354). Under a CMV, early enhancer plus chicken β actin promoter (CAG) MUC16c354 was well expressed in many organs, including the brain, colon, heart, kidney, liver, lung, ovary, and spleen. MUC16c354 transgenic animals appear to be viable, fertile, and have a normal lifespan. However, when crossed with p53-deficient mice, the MUC16c354:p53+/- progeny displayed a higher frequency of spontaneous tumor development compared to p53+/- mice alone. We conclude that the carboxy-terminal portion of the MUC16/CA125 protein is oncogenic in NIH/3T3 cells, increases invasive tumor properties, activates the AKT and ERK pathways, and contributes to the biologic properties of ovarian cancer. Public Library of Science 2015-05-12 /pmc/articles/PMC4429113/ /pubmed/25965947 http://dx.doi.org/10.1371/journal.pone.0126633 Text en © 2015 Rao et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Rao, Thapi D. Tian, Huasong Ma, Xun Yan, Xiujun Thapi, Sahityasri Schultz, Nikolaus Rosales, Nestor Monette, Sebastien Wang, Amy Hyman, David M. Levine, Douglas A. Solit, David Spriggs, David R.
spellingShingle	Rao, Thapi D. Tian, Huasong Ma, Xun Yan, Xiujun Thapi, Sahityasri Schultz, Nikolaus Rosales, Nestor Monette, Sebastien Wang, Amy Hyman, David M. Levine, Douglas A. Solit, David Spriggs, David R. Expression of the Carboxy-Terminal Portion of MUC16/CA125 Induces Transformation and Tumor Invasion
author_facet	Rao, Thapi D. Tian, Huasong Ma, Xun Yan, Xiujun Thapi, Sahityasri Schultz, Nikolaus Rosales, Nestor Monette, Sebastien Wang, Amy Hyman, David M. Levine, Douglas A. Solit, David Spriggs, David R.
author_sort	Rao, Thapi D.
title	Expression of the Carboxy-Terminal Portion of MUC16/CA125 Induces Transformation and Tumor Invasion
title_short	Expression of the Carboxy-Terminal Portion of MUC16/CA125 Induces Transformation and Tumor Invasion
title_full	Expression of the Carboxy-Terminal Portion of MUC16/CA125 Induces Transformation and Tumor Invasion
title_fullStr	Expression of the Carboxy-Terminal Portion of MUC16/CA125 Induces Transformation and Tumor Invasion
title_full_unstemmed	Expression of the Carboxy-Terminal Portion of MUC16/CA125 Induces Transformation and Tumor Invasion
title_sort	expression of the carboxy-terminal portion of muc16/ca125 induces transformation and tumor invasion
description	The CA125 antigen is found in the serum of many patients with serous ovarian cancer and has been widely used as a disease marker. CA125 has been shown to be an independent factor for clinical outcome in this disease. In The Cancer Genome Atlas ovarian cancer project, MUC16 expression levels are frequently increased, and the highest levels of MUC16 expression are linked to a significantly worse survival. To examine the biologic effect of the proximal portion of MUC16/CA125, NIH/3T3 (3T3) fibroblast cell lines were stably transfected with the carboxy elements of MUC16. As few as 114 amino acids from the carboxy-terminal portion of MUC16 were sufficient to increase soft agar growth, promote matrigel invasion, and increase the rate of tumor growth in athymic nude mice. Transformation with carboxy elements of MUC16 was associated with activation of the AKT and ERK pathways. MUC16 transformation was associated with up-regulation of a number of metastases and invasion gene transcripts, including IL-1β, MMP2, and MMP9. All observed oncogenic changes were exclusively dependent on the extracellular “ectodomain” of MUC16. The biologic impact of MUC16 was also explored through the creation of a transgenic mouse model expressing 354 amino acids of the carboxy-terminal portion of MUC16 (MUC16c354). Under a CMV, early enhancer plus chicken β actin promoter (CAG) MUC16c354 was well expressed in many organs, including the brain, colon, heart, kidney, liver, lung, ovary, and spleen. MUC16c354 transgenic animals appear to be viable, fertile, and have a normal lifespan. However, when crossed with p53-deficient mice, the MUC16c354:p53+/- progeny displayed a higher frequency of spontaneous tumor development compared to p53+/- mice alone. We conclude that the carboxy-terminal portion of the MUC16/CA125 protein is oncogenic in NIH/3T3 cells, increases invasive tumor properties, activates the AKT and ERK pathways, and contributes to the biologic properties of ovarian cancer.
publisher	Public Library of Science
publishDate	2015
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4429113/
_version_	1613222529721171968

Expression of the Carboxy-Terminal Portion of MUC16/CA125 Induces Transformation and Tumor Invasion

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