Sulfiredoxin Promotes Cancer Cell Invasion through Regulation of the miR143-Fascin Axis

ABSTRACT

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 3′ 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.

KEYWORDS:

• antioxidant
• enzyme mechanism
• oxidative stress

Declaration of Interests

The authors declare no conflict of interest.

SUPPLEMENTAL MATERIAL

Supplemental material is available online only.

ACKNOWLEDGMENTS

This research was supported by the National Institutes of Health (NCI grant R01CA222596), the Department of Defense (grant W81XWH-16-1-0203), the American Cancer Society (grant RSG-16-213-01-TBE), and the Kentucky Lung Cancer Research Program (grant KLCRP2016). This research was also supported by the Biostatistics and Bioinformatics Shared Resource and the Oncogenomics Shared Resource of the University of Kentucky Markey Cancer Center (grant P30CA177558).

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