KPNA3 promotes epithelial-mesenchymal transition by regulating TGF-β and AKT signaling pathways in MDA-MB-231, a triple-negative breast cancer cell line
2
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
Karyopherin-α3 (KPNA3), a karyopherin- α isoform, is intimatelyassociated with metastatic progression via epithelial-mesenchymaltransition (EMT). However, the molecular mechanismunderlying how KPNA3 acts as an EMT inducer remains to beelucidated. In this report, we identified that KPNA3 was significantlyupregulated in cancer cells, particularly in triple-negativebreast cancer, and its knockdown resulted in the suppressionof cell proliferation and metastasis. The comprehensivetranscriptome analysis from KPNA3 knockdown cells indicatedthat KPNA3 is involved in the regulation of numerous EMTrelatedgenes, including the downregulation of GATA3 andE-cadherin and the up-regulation of HAS2. Moreover, it wasfound that KPNA3 EMT-mediated metastasis can be achievedby TGF-β or AKT signaling pathways; this suggests that thenovel independent signaling pathways KPNA3-TGF-β-GATA3-HAS2/E-cadherin and KPNA3-AKT-HAS2/E-cadherin are involvedin the EMT-mediated progress of TNBC MDA-MB-231 cells. These findings provide new insights into the divergent EMTinducibility of KPNA3 according to cell and cancer type.
Abstract
Karyopherin-α3 (KPNA3), a karyopherin- α isoform, is intimatelyassociated with metastatic progression via epithelial-mesenchymaltransition (EMT). However, the molecular mechanismunderlying how KPNA3 acts as an EMT inducer remains to beelucidated. In this report, we identified that KPNA3 was significantlyupregulated in cancer cells, particularly in triple-negativebreast cancer, and its knockdown resulted in the suppressionof cell proliferation and metastasis. The comprehensivetranscriptome analysis from KPNA3 knockdown cells indicatedthat KPNA3 is involved in the regulation of numerous EMTrelatedgenes, including the downregulation of GATA3 andE-cadherin and the up-regulation of HAS2. Moreover, it wasfound that KPNA3 EMT-mediated metastasis can be achievedby TGF-β or AKT signaling pathways; this suggests that thenovel independent signaling pathways KPNA3-TGF-β-GATA3-HAS2/E-cadherin and KPNA3-AKT-HAS2/E-cadherin are involvedin the EMT-mediated progress of TNBC MDA-MB-231 cells. These findings provide new insights into the divergent EMTinducibility of KPNA3 according to cell and cancer type.
참고문헌 (21)
- Nieto MA, "Emt : 2016", Cell, 166, pp.21~45 (2016)
- Lamouille S, "Molecular mechanisms of epithelial-mesenchymal transition", Nat Rev Mol Cell Biol, 15, pp.178~196 (2014)
- Cingolani G, "Structure of importin-beta bound to the IBB domain of importin-alpha", Nature, 399, pp.221~229 (1999)
- Mehmood R, "Molecular profiling of nucleocytoplasmic transport factor genes in breast cancer", Heliyon, 7, pp.e06039~ (2021)
- Hu B, "KPNA3 confers sorafenib resistance to advanced hepatocellular carcinoma via TWIST regulated epithelial-mesenchymal transition", J Cancer, 10, pp.3914~3925 (2019)
- Groger CJ, "Meta-analysis of gene expression signatures defining the epithelial to mesenchymal transition during cancer progression", PLoS One, 7, pp.e51136~ (2012)
- Dai X, "Breast cancer cell line classification and its relevance with breast tumor subtyping", J Cancer, 8, pp.3131~3141 (2017)
- Yan W, "GATA3 inhibits breast cancer metastasis through the reversal of epithelial-mesenchymal transition", J Biol Chem, 285, pp.14042~14051 (2010)
- Liu S, "TGF-β signaling : A complex role in tumorigenesis(review)", Mol Med Rep, 17, pp.699~704 (2018)
- Caon I, "Revisiting the hallmarks of cancer : the role of hyaluronan", Semin Cancer Biol, 62, pp.9~19 (2020)
- Matsumoto K, "Distinct interaction of versican", PG-M with hyaluronan and link protein, 2003, pp.278, 41205~41212
- Graziani G, "Neuropilin-1 as therapeutic target for malignant melanoma", Front Oncol, 5, pp.125~ (2015)
- Li J, "Cardiac tissue-restricted deletion of plakoglobin results in progressive cardiomyopathy and activation of β-catenin signaling", Mol Cell Biol, 31, pp.1134~1144 (2011)
- Yang J, "Epithelial-mesenchymal transition : at the crossroads of development and tumor metastasis", Dev Cell, 14, pp.818~829 (2008)
- Radisky ES, "Matrix metalloproteinase-induced epithelial-mesenchymal transition in breast cancer", J Mammary Gland Biol Neoplasia, 15, pp.201~212 (2010)
- Geervliet E, "Matrix metalloproteinases as potential biomarkers and therapeutic targets in liver diseases", Cells, 9, pp.1212~ (2020)
- Liu S, "Targeting TGFβ signal transduction for cancer therapy", Signal Transduct Target Ther, 6, pp.8~ (2021)
- Heath VL, "TGF-β1 down-regulates Th2 development and results in decreased IL-4-induced STAT6 activation and GATA-3 expression", Eur J Immunol, 30, pp.2639~2649 (2000)
- Zhang YE, "Non-Smad pathways in TGF-β signaling", Cell Res, 19, pp.128~139 (2009)
- Zhu X, "Ophiopogonin D suppresses TGF-β1-mediated metastatic behavior of MDAMB-231 breast carcinoma cells via regulating ITGB1", FAK, AKT, pp.β-catenin, MMP-9 signaling axis[DOI]
- Boldbaatar A, "Eupatolide inhibits the TGF-β1-induced migration of breast cancer cells via downregulation of SMAD3 phosphorylation and transcriptional repression of ALK5", Oncol Lett, 14, pp.6031~6039 (2017)