TY - JOUR
T1 - Sulfiredoxin Promotes Cancer Cell Invasion through Regulation of the miR143-Fascin Axis
AU - Jiang, Hong
AU - Thapa, Pratik
AU - Ding, Na
AU - Hao, Yanning
AU - Alshahrani, Aziza
AU - Wang, Chi
AU - Evers, B. Mark
AU - Wei, Qiou
N1 - Publisher Copyright:
Copyright © 2022 American Society for Microbiology. All Rights Reserved.
PY - 2022/5
Y1 - 2022/5
N2 - Intracellular antioxidant enzymes are critical for maintenance of redox homeostasis, but whether and how they contribute to the malignancy of cancer cells remains poorly understood. Sulfiredoxin (Srx) is a unique oxidoreductase in that it not only restores peroxidase activity of peroxiredoxins (Prxs) but also functions as a pivotal stimulator of oncogenic signaling. We found that abnormally high level of Srx promotes colorectal cancer (CRC) malignancy by stimulating gelatin degradation, invadopodia formation, and cell invasion. Fascin, an actin-bundling protein, was discovered and validated as one of the critical downstream targets of Srx activation. We demonstrated that depletion of Srx in CRC cells leads to upregulation of miR-143-3p, which mediates degradation of fascin mRNA through binding to conserved sites within the 39 untranslated region (UTR). Depletion of fascin in CRC cells recapitulates the effect of Srx loss, and restoration of fascin in Srx-depleted cells by miR-143-3p inhibitor or overexpression rescues defects in cell invasion. Therefore, our data demonstrate that the Srx-miR143-fascin axis plays a key role in promoting the malignancy of human CRC cells. In the future, the Srx-miR143-fascin axis can be used as a functional pathway to evaluate the efficacy of therapeutic drugs or be targeted to develop promising chemotherapeutics for treatment of CRC patients.
AB - Intracellular antioxidant enzymes are critical for maintenance of redox homeostasis, but whether and how they contribute to the malignancy of cancer cells remains poorly understood. Sulfiredoxin (Srx) is a unique oxidoreductase in that it not only restores peroxidase activity of peroxiredoxins (Prxs) but also functions as a pivotal stimulator of oncogenic signaling. We found that abnormally high level of Srx promotes colorectal cancer (CRC) malignancy by stimulating gelatin degradation, invadopodia formation, and cell invasion. Fascin, an actin-bundling protein, was discovered and validated as one of the critical downstream targets of Srx activation. We demonstrated that depletion of Srx in CRC cells leads to upregulation of miR-143-3p, which mediates degradation of fascin mRNA through binding to conserved sites within the 39 untranslated region (UTR). Depletion of fascin in CRC cells recapitulates the effect of Srx loss, and restoration of fascin in Srx-depleted cells by miR-143-3p inhibitor or overexpression rescues defects in cell invasion. Therefore, our data demonstrate that the Srx-miR143-fascin axis plays a key role in promoting the malignancy of human CRC cells. In the future, the Srx-miR143-fascin axis can be used as a functional pathway to evaluate the efficacy of therapeutic drugs or be targeted to develop promising chemotherapeutics for treatment of CRC patients.
KW - Antioxidant
KW - Enzyme mechanism
KW - Oxidative stress
UR - http://www.scopus.com/inward/record.url?scp=85130765741&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85130765741&partnerID=8YFLogxK
U2 - 10.1128/mcb.00051-22
DO - 10.1128/mcb.00051-22
M3 - Article
C2 - 35412358
AN - SCOPUS:85130765741
SN - 0270-7306
VL - 42
JO - Molecular and Cellular Biology
JF - Molecular and Cellular Biology
IS - 5
ER -