Nck-associated protein 1 associates with HSP90 to drive metastasis in human non-small-cell lung cancer

Yuanping Xiong, Leilei He, Chloe Shay, Liwei Lang, Jenni Loveless, Jieqing Yu, Ron Chemmalakuzhy, Hongqun Jiang, Manran Liu, Yong Teng

Research output: Contribution to journalArticle

Abstract

Background: Metastatic lung cancer is a life-threatening condition that develops when cancer in another area of the body metastasizes, or spreads, to the lung. Despite advances in our understanding of primary lung oncogenesis, the biological basis driving the progression from primary to metastatic lung cancer remains poorly characterized. Methods: Genetic knockdown of the particular genes in cancer cells were achieved by lentiviral-mediated interference. Invasion potential was determined by Matrigel and three-dimensional invasion. The secretion of matrix metalloproteinase 2 (MMP2) and MMP9 were measured by ELISA. Protein levels were assessed by Western blotting and immunohistochemistry. Protein-protein interactions were determined by immunoprecipitation. An experimental mouse model was generated to investigate the gene regulation in tumor growth and metastasis. Results: Nck-associated protein 1 (NAP1/NCKAP1) is highly expressed in primary non-small-cell lung cancer (NSCLC) when compared with adjacent normal lung tissues, and its expression levels are strongly associated with the histologic tumor grade, metastasis and poor survival rate of NSCLC patients. Overexpression of NAP1 in lowly invasive NSCLC cells enhances MMP9 secretion and invasion potential, whereas NAP1 silencing in highly invasive NSCLC cells produces opposing effects in comparison. Mechanistic studies further reveal that the binding of NAP1 to the cellular chaperone heat shock protein 90 (HSP90) is required for its protein stabilization, and NAP1 plays an essential role in HSP90-mediated invasion and metastasis by provoking MMP9 activation and the epithelial-to-mesenchymal transition in NSCLC cells. Conclusions: Our insights demonstrate the importance and functional regulation of the HSP90-NAP1 protein complex in cancer metastatic signaling, which spur new avenues to target this interaction as a novel approach to block NSCLC metastasis.

Original languageEnglish (US)
Article number122
JournalJournal of Experimental and Clinical Cancer Research
Volume38
Issue number1
DOIs
StatePublished - Mar 11 2019

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HSP90 Heat-Shock Proteins
Non-Small Cell Lung Carcinoma
Neoplasm Metastasis
Proteins
Lung
Lung Neoplasms
Neoplasms
Gene Knockdown Techniques
Epithelial-Mesenchymal Transition
Neoplasm Genes
Matrix Metalloproteinase 2
Immunoprecipitation
Nck protein
Carcinogenesis
Theoretical Models
Survival Rate
Western Blotting
Enzyme-Linked Immunosorbent Assay
Immunohistochemistry
Growth

Keywords

  • HSP90
  • NCKAP1/NAP1
  • lung cancer
  • metastasis
  • protein stability

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Nck-associated protein 1 associates with HSP90 to drive metastasis in human non-small-cell lung cancer. / Xiong, Yuanping; He, Leilei; Shay, Chloe; Lang, Liwei; Loveless, Jenni; Yu, Jieqing; Chemmalakuzhy, Ron; Jiang, Hongqun; Liu, Manran; Teng, Yong.

In: Journal of Experimental and Clinical Cancer Research, Vol. 38, No. 1, 122, 11.03.2019.

Research output: Contribution to journalArticle

Xiong, Yuanping ; He, Leilei ; Shay, Chloe ; Lang, Liwei ; Loveless, Jenni ; Yu, Jieqing ; Chemmalakuzhy, Ron ; Jiang, Hongqun ; Liu, Manran ; Teng, Yong. / Nck-associated protein 1 associates with HSP90 to drive metastasis in human non-small-cell lung cancer. In: Journal of Experimental and Clinical Cancer Research. 2019 ; Vol. 38, No. 1.
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abstract = "Background: Metastatic lung cancer is a life-threatening condition that develops when cancer in another area of the body metastasizes, or spreads, to the lung. Despite advances in our understanding of primary lung oncogenesis, the biological basis driving the progression from primary to metastatic lung cancer remains poorly characterized. Methods: Genetic knockdown of the particular genes in cancer cells were achieved by lentiviral-mediated interference. Invasion potential was determined by Matrigel and three-dimensional invasion. The secretion of matrix metalloproteinase 2 (MMP2) and MMP9 were measured by ELISA. Protein levels were assessed by Western blotting and immunohistochemistry. Protein-protein interactions were determined by immunoprecipitation. An experimental mouse model was generated to investigate the gene regulation in tumor growth and metastasis. Results: Nck-associated protein 1 (NAP1/NCKAP1) is highly expressed in primary non-small-cell lung cancer (NSCLC) when compared with adjacent normal lung tissues, and its expression levels are strongly associated with the histologic tumor grade, metastasis and poor survival rate of NSCLC patients. Overexpression of NAP1 in lowly invasive NSCLC cells enhances MMP9 secretion and invasion potential, whereas NAP1 silencing in highly invasive NSCLC cells produces opposing effects in comparison. Mechanistic studies further reveal that the binding of NAP1 to the cellular chaperone heat shock protein 90 (HSP90) is required for its protein stabilization, and NAP1 plays an essential role in HSP90-mediated invasion and metastasis by provoking MMP9 activation and the epithelial-to-mesenchymal transition in NSCLC cells. Conclusions: Our insights demonstrate the importance and functional regulation of the HSP90-NAP1 protein complex in cancer metastatic signaling, which spur new avenues to target this interaction as a novel approach to block NSCLC metastasis.",
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AU - Xiong, Yuanping

AU - He, Leilei

AU - Shay, Chloe

AU - Lang, Liwei

AU - Loveless, Jenni

AU - Yu, Jieqing

AU - Chemmalakuzhy, Ron

AU - Jiang, Hongqun

AU - Liu, Manran

AU - Teng, Yong

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N2 - Background: Metastatic lung cancer is a life-threatening condition that develops when cancer in another area of the body metastasizes, or spreads, to the lung. Despite advances in our understanding of primary lung oncogenesis, the biological basis driving the progression from primary to metastatic lung cancer remains poorly characterized. Methods: Genetic knockdown of the particular genes in cancer cells were achieved by lentiviral-mediated interference. Invasion potential was determined by Matrigel and three-dimensional invasion. The secretion of matrix metalloproteinase 2 (MMP2) and MMP9 were measured by ELISA. Protein levels were assessed by Western blotting and immunohistochemistry. Protein-protein interactions were determined by immunoprecipitation. An experimental mouse model was generated to investigate the gene regulation in tumor growth and metastasis. Results: Nck-associated protein 1 (NAP1/NCKAP1) is highly expressed in primary non-small-cell lung cancer (NSCLC) when compared with adjacent normal lung tissues, and its expression levels are strongly associated with the histologic tumor grade, metastasis and poor survival rate of NSCLC patients. Overexpression of NAP1 in lowly invasive NSCLC cells enhances MMP9 secretion and invasion potential, whereas NAP1 silencing in highly invasive NSCLC cells produces opposing effects in comparison. Mechanistic studies further reveal that the binding of NAP1 to the cellular chaperone heat shock protein 90 (HSP90) is required for its protein stabilization, and NAP1 plays an essential role in HSP90-mediated invasion and metastasis by provoking MMP9 activation and the epithelial-to-mesenchymal transition in NSCLC cells. Conclusions: Our insights demonstrate the importance and functional regulation of the HSP90-NAP1 protein complex in cancer metastatic signaling, which spur new avenues to target this interaction as a novel approach to block NSCLC metastasis.

AB - Background: Metastatic lung cancer is a life-threatening condition that develops when cancer in another area of the body metastasizes, or spreads, to the lung. Despite advances in our understanding of primary lung oncogenesis, the biological basis driving the progression from primary to metastatic lung cancer remains poorly characterized. Methods: Genetic knockdown of the particular genes in cancer cells were achieved by lentiviral-mediated interference. Invasion potential was determined by Matrigel and three-dimensional invasion. The secretion of matrix metalloproteinase 2 (MMP2) and MMP9 were measured by ELISA. Protein levels were assessed by Western blotting and immunohistochemistry. Protein-protein interactions were determined by immunoprecipitation. An experimental mouse model was generated to investigate the gene regulation in tumor growth and metastasis. Results: Nck-associated protein 1 (NAP1/NCKAP1) is highly expressed in primary non-small-cell lung cancer (NSCLC) when compared with adjacent normal lung tissues, and its expression levels are strongly associated with the histologic tumor grade, metastasis and poor survival rate of NSCLC patients. Overexpression of NAP1 in lowly invasive NSCLC cells enhances MMP9 secretion and invasion potential, whereas NAP1 silencing in highly invasive NSCLC cells produces opposing effects in comparison. Mechanistic studies further reveal that the binding of NAP1 to the cellular chaperone heat shock protein 90 (HSP90) is required for its protein stabilization, and NAP1 plays an essential role in HSP90-mediated invasion and metastasis by provoking MMP9 activation and the epithelial-to-mesenchymal transition in NSCLC cells. Conclusions: Our insights demonstrate the importance and functional regulation of the HSP90-NAP1 protein complex in cancer metastatic signaling, which spur new avenues to target this interaction as a novel approach to block NSCLC metastasis.

KW - HSP90

KW - NCKAP1/NAP1

KW - lung cancer

KW - metastasis

KW - protein stability

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