Article Text
PDF
Abstract
Introduction/Background Lymph node metastasis (LNM), the dominated metastatic pattern in cervical cancer, is a profound prognostic factor and is important in treatment decision-making. Therefore, to unveil the mechanism of this process and to explore new target for cancer treatment can be of great significance.
Methodology We performed in vivo genome-wide CRISPR/Cas9 knockout screening to identify key regulators of cervical cancer lymph node metastasis. We next investigated the molecular mechanism of DUSP4 deficiency in promoting cervical cancer metastasis by reverse phase protein array (RPPA), immunoprecipitation and LC-MS.
Results We found that the DUSP family member, DUSP4 and DUSP5, stood out as the top hits in the screening. We confirmed these findings in cervical cancer patient samples by immunohistochemistry. The expression of DUSP4 was dramatically decreased in LNM and the deficiency of DUSP4 enhances metastasis of cervical cancer cell in vitro. The notable finding is that interaction between DUSP4 and AXL might be a novel mechanism in control cervical cancer lymph node metastasis. DUSP4 induces ubiquitination and proteasomal degradation of AXL via TRIM21, which is a noted E3 ubiquitin-protein ligase. Finally, the efficacy of AXL inhibitor in hindering LNM were validated in vivo.
Conclusion These data suggest that cross-talk of DUSP4 and AXL plays an important role in regulation of cervical cancer LNM, and AXL inhibitor successfully impedes the process, which further contributes to treatment of advanced cervical cancer.
Disclosures There is no conflict of interest.
