Mitochondrial Respiratory Defect Enhances Hepatoma Cell Invasiveness via STAT3/NFE2L1/STX12 Axis
Mitochondrial respiratory defects have been implicated in cancer progression and metastasis, but how they control tumor cell aggressiveness remains unclear. Here, we demonstrate that a mitochondrial respiratory defect induces nuclear factor-erythroid 2 like 1 (NFE2L1) expression at the transcription...
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doaj-f891c941b2c142f08020ef6279d4685d2020-11-25T03:26:01ZengMDPI AGCancers2072-66942020-09-01122632263210.3390/cancers12092632Mitochondrial Respiratory Defect Enhances Hepatoma Cell Invasiveness via STAT3/NFE2L1/STX12 AxisYoung-Kyoung Lee0So Mee Kwon1Eun-beom Lee2Gyeong-Hyeon Kim3Seongki Min4Sun-Mi Hong5Hee-Jung Wang6Dong Min Lee7Kyeong Sook Choi8Tae Jun Park9Gyesoon Yoon10Department of Biochemistry, Ajou University School of Medicine, Suwon 16499, KoreaDepartment of Biochemistry, Ajou University School of Medicine, Suwon 16499, KoreaDepartment of Biochemistry, Ajou University School of Medicine, Suwon 16499, KoreaDepartment of Biochemistry, Ajou University School of Medicine, Suwon 16499, KoreaDepartment of Biochemistry, Ajou University School of Medicine, Suwon 16499, KoreaDepartment of Biochemistry, Ajou University School of Medicine, Suwon 16499, KoreaDepartment of Surgery, Ajou University School of Medicine, Suwon 16499, KoreaDepartment of Biochemistry, Ajou University School of Medicine, Suwon 16499, KoreaDepartment of Biochemistry, Ajou University School of Medicine, Suwon 16499, KoreaDepartment of Biochemistry, Ajou University School of Medicine, Suwon 16499, KoreaDepartment of Biochemistry, Ajou University School of Medicine, Suwon 16499, KoreaMitochondrial respiratory defects have been implicated in cancer progression and metastasis, but how they control tumor cell aggressiveness remains unclear. Here, we demonstrate that a mitochondrial respiratory defect induces nuclear factor-erythroid 2 like 1 (NFE2L1) expression at the transcriptional level via reactive oxygen species (ROS)-mediated STAT3 activation. We identified syntaxin 12 (STX12) as an effective downstream target of NFE2L1 by performing cDNA microarray analysis after the overexpression and depletion of NFE2L1 in hepatoma cells. Bioinformatics analysis of The Cancer Genome Atlas Liver Hepatocellular carcinoma (TCGA-LIHC) open database (<i>n</i> = 371) also revealed a significant positive association (<i>r</i> = 0.3, <i>p</i> = 2.49 × 10<sup>−9</sup>) between NFE2L1 and STX12 expression. We further demonstrated that STX12 is upregulated through the ROS/STAT3/NFE2L1 axis and is a key downstream effector of NFE2L1 in modulating hepatoma cell invasiveness. In addition, gene enrichment analysis of TCGA-LIHC also showed that epithelial–mesenchymal transition (EMT)-related core genes are significantly upregulated in tumors co-expressing NFE2L1 and STX12. The positive association between NFE2L1 and STX12 expression was validated by immunohistochemistry of the hepatocellular carcinoma tissue array. Finally, higher EMT gene enrichment and worse overall survival (<i>p</i> = 0.043) were observed in the NFE2L1 and STX12 co-expression group with mitochondrial defect, as indicated by low NDUFA9 expression. Collectively, our results indicate that NFE2L1 is a key mitochondrial retrograde signaling-mediated primary gene product enhancing hepatoma cell invasiveness via STX12 expression and promoting liver cancer progression.https://www.mdpi.com/2072-6694/12/9/2632hepatocellular carcinomamitochondrial defectNFE2L1retrograde signalingSTAT3STX12 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Young-Kyoung Lee So Mee Kwon Eun-beom Lee Gyeong-Hyeon Kim Seongki Min Sun-Mi Hong Hee-Jung Wang Dong Min Lee Kyeong Sook Choi Tae Jun Park Gyesoon Yoon |
spellingShingle |
Young-Kyoung Lee So Mee Kwon Eun-beom Lee Gyeong-Hyeon Kim Seongki Min Sun-Mi Hong Hee-Jung Wang Dong Min Lee Kyeong Sook Choi Tae Jun Park Gyesoon Yoon Mitochondrial Respiratory Defect Enhances Hepatoma Cell Invasiveness via STAT3/NFE2L1/STX12 Axis Cancers hepatocellular carcinoma mitochondrial defect NFE2L1 retrograde signaling STAT3 STX12 |
author_facet |
Young-Kyoung Lee So Mee Kwon Eun-beom Lee Gyeong-Hyeon Kim Seongki Min Sun-Mi Hong Hee-Jung Wang Dong Min Lee Kyeong Sook Choi Tae Jun Park Gyesoon Yoon |
author_sort |
Young-Kyoung Lee |
title |
Mitochondrial Respiratory Defect Enhances Hepatoma Cell Invasiveness via STAT3/NFE2L1/STX12 Axis |
title_short |
Mitochondrial Respiratory Defect Enhances Hepatoma Cell Invasiveness via STAT3/NFE2L1/STX12 Axis |
title_full |
Mitochondrial Respiratory Defect Enhances Hepatoma Cell Invasiveness via STAT3/NFE2L1/STX12 Axis |
title_fullStr |
Mitochondrial Respiratory Defect Enhances Hepatoma Cell Invasiveness via STAT3/NFE2L1/STX12 Axis |
title_full_unstemmed |
Mitochondrial Respiratory Defect Enhances Hepatoma Cell Invasiveness via STAT3/NFE2L1/STX12 Axis |
title_sort |
mitochondrial respiratory defect enhances hepatoma cell invasiveness via stat3/nfe2l1/stx12 axis |
publisher |
MDPI AG |
series |
Cancers |
issn |
2072-6694 |
publishDate |
2020-09-01 |
description |
Mitochondrial respiratory defects have been implicated in cancer progression and metastasis, but how they control tumor cell aggressiveness remains unclear. Here, we demonstrate that a mitochondrial respiratory defect induces nuclear factor-erythroid 2 like 1 (NFE2L1) expression at the transcriptional level via reactive oxygen species (ROS)-mediated STAT3 activation. We identified syntaxin 12 (STX12) as an effective downstream target of NFE2L1 by performing cDNA microarray analysis after the overexpression and depletion of NFE2L1 in hepatoma cells. Bioinformatics analysis of The Cancer Genome Atlas Liver Hepatocellular carcinoma (TCGA-LIHC) open database (<i>n</i> = 371) also revealed a significant positive association (<i>r</i> = 0.3, <i>p</i> = 2.49 × 10<sup>−9</sup>) between NFE2L1 and STX12 expression. We further demonstrated that STX12 is upregulated through the ROS/STAT3/NFE2L1 axis and is a key downstream effector of NFE2L1 in modulating hepatoma cell invasiveness. In addition, gene enrichment analysis of TCGA-LIHC also showed that epithelial–mesenchymal transition (EMT)-related core genes are significantly upregulated in tumors co-expressing NFE2L1 and STX12. The positive association between NFE2L1 and STX12 expression was validated by immunohistochemistry of the hepatocellular carcinoma tissue array. Finally, higher EMT gene enrichment and worse overall survival (<i>p</i> = 0.043) were observed in the NFE2L1 and STX12 co-expression group with mitochondrial defect, as indicated by low NDUFA9 expression. Collectively, our results indicate that NFE2L1 is a key mitochondrial retrograde signaling-mediated primary gene product enhancing hepatoma cell invasiveness via STX12 expression and promoting liver cancer progression. |
topic |
hepatocellular carcinoma mitochondrial defect NFE2L1 retrograde signaling STAT3 STX12 |
url |
https://www.mdpi.com/2072-6694/12/9/2632 |
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