PSPC1-interchanged interactions with PTK6 and β-catenin synergize oncogenic subcellular translocations and tumor progression

Yaw Dong Lang, Hsin Yi Chen, Chun Ming Ho, Jou Ho Shih, En Chi Hsu, Roger Shen, Yu Ching Lee, Jyun Wei Chen, Cheng Yen Wu, Hsi Wen Yeh, Ruey Hwa Chen, Yuh Shan Jou

研究成果: 雜誌貢獻文章

1 引文 (Scopus)

摘要

Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide due to metastasis. Paraspeckle component 1 (PSPC1) upregulation has been identified as an HCC pro-metastatic activator associated with poor patient prognosis, but with a lack of targeting strategy. Here, we report that PSPC1, a nuclear substrate of PTK6, sequesters PTK6 in the nucleus and loses its metastasis driving capability. Conversely, PSPC1 upregulation or PSPC1-Y523F mutation promotes epithelial-mesenchymal transition, stemness, and metastasis via cytoplasmic translocation of active PTK6 and nuclear translocation of β-catenin, which interacts with PSPC1 to augment Wnt3a autocrine signaling. The aberrant nucleocytoplasmic shuttling of active PTK6/β-catenin is reversed by expressing the PSPC1 C-terminal interacting domain (PSPC1-CT131), thereby suppressing PSPC1/PTK6/β-catenin-activated metastasis to prolong the survival of HCC orthotopic mice. Thus, PSPC1 is the contextual determinant of the oncogenic switch of PTK6/β-catenin subcellular localizations, and PSPC1-CT131 functions as a dual inhibitor of PSPC1 and PTK6 with potential for improving cancer therapy.
原文英語
文章編號5716
期刊Nature Communications
10
發行號1
DOIs
出版狀態已發佈 - 十二月 1 2019

指紋

Catenins
progressions
Tumors
tumors
Neoplasm Metastasis
Hepatocellular Carcinoma
Neoplasms
Up-Regulation
metastasis
Autocrine Communication
interactions
cancer
Epithelial-Mesenchymal Transition
Switches
Mutation
Survival
Substrates
prognosis
mutations
determinants

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

引用此文

PSPC1-interchanged interactions with PTK6 and β-catenin synergize oncogenic subcellular translocations and tumor progression. / Lang, Yaw Dong; Chen, Hsin Yi; Ho, Chun Ming; Shih, Jou Ho; Hsu, En Chi; Shen, Roger; Lee, Yu Ching; Chen, Jyun Wei; Wu, Cheng Yen; Yeh, Hsi Wen; Chen, Ruey Hwa; Jou, Yuh Shan.

於: Nature Communications, 卷 10, 編號 1, 5716, 01.12.2019.

研究成果: 雜誌貢獻文章

Lang, Yaw Dong ; Chen, Hsin Yi ; Ho, Chun Ming ; Shih, Jou Ho ; Hsu, En Chi ; Shen, Roger ; Lee, Yu Ching ; Chen, Jyun Wei ; Wu, Cheng Yen ; Yeh, Hsi Wen ; Chen, Ruey Hwa ; Jou, Yuh Shan. / PSPC1-interchanged interactions with PTK6 and β-catenin synergize oncogenic subcellular translocations and tumor progression. 於: Nature Communications. 2019 ; 卷 10, 編號 1.
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abstract = "Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide due to metastasis. Paraspeckle component 1 (PSPC1) upregulation has been identified as an HCC pro-metastatic activator associated with poor patient prognosis, but with a lack of targeting strategy. Here, we report that PSPC1, a nuclear substrate of PTK6, sequesters PTK6 in the nucleus and loses its metastasis driving capability. Conversely, PSPC1 upregulation or PSPC1-Y523F mutation promotes epithelial-mesenchymal transition, stemness, and metastasis via cytoplasmic translocation of active PTK6 and nuclear translocation of β-catenin, which interacts with PSPC1 to augment Wnt3a autocrine signaling. The aberrant nucleocytoplasmic shuttling of active PTK6/β-catenin is reversed by expressing the PSPC1 C-terminal interacting domain (PSPC1-CT131), thereby suppressing PSPC1/PTK6/β-catenin-activated metastasis to prolong the survival of HCC orthotopic mice. Thus, PSPC1 is the contextual determinant of the oncogenic switch of PTK6/β-catenin subcellular localizations, and PSPC1-CT131 functions as a dual inhibitor of PSPC1 and PTK6 with potential for improving cancer therapy.",
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