Smith-Díaz Carlos C, Kumar Abhishek, Das Andrew, Pace Paul, Chitcholtan Kenny, Magon Nicholas J, Hossain Sultana Mehbuba, Eccles Michael R, Winterbourn Christine C, Paumann-Page Martina
Mātai Hāora, Centre for Redox Biology and Medicine, University of Otago Christchurch, Christchurch, New Zealand.
Centre for Protein Research, Research Infrastructure Centre, University of Otago, Dunedin, New Zealand.
Free Radic Biol Med. 2025 Mar 1;229:427-440. doi: 10.1016/j.freeradbiomed.2025.01.007. Epub 2025 Jan 8.
Cutaneous melanoma is a highly invasive, heterogeneous and treatment resistant cancer. It's ability to dynamically shift between transcriptional states or phenotypes results in an adaptive cell plasticity that may drive cancer cell invasion or the development of therapy resistance. The expression of peroxidasin (PXDN), an extracellular matrix peroxidase, has been proposed to be associated with the invasive metastatic melanoma phenotype. We have confirmed this association by analysing the transcriptomes of 70 metastatic melanoma cell lines with variable levels of PXDN expression. This analysis highlighted a strong association between high PXDN expression and the undifferentiated invasive melanoma phenotype. To assess the functional role of PXDN in melanoma invasion, we performed a knockout of PXDN in a highly invasive cell line (NZM40). PXDN knockout decreased the invasive potential by ∼50 % and decreased the expression of epithelial-mesenchymal transition and invasive marker genes as determined by RNAseq and substantiated by proteomics analysis. Bioinformatics analysis of differentially expressed genes following PXDN knockout highlighted decreases in genes linked to extracellular matrix formation, organization and degradation as well as signalling pathways such as the WNT pathway. This study provides compelling evidence that PXDN plays a functional role in melanoma invasion by promoting an invasive, mesenchymal-like transcriptional phenotype.
皮肤黑色素瘤是一种具有高度侵袭性、异质性且对治疗有抗性的癌症。它在转录状态或表型之间动态转换的能力导致了一种适应性细胞可塑性，这可能驱动癌细胞的侵袭或治疗抗性的发展。细胞外基质过氧化物酶过氧化物酶蛋白（PXDN）的表达已被认为与侵袭性转移性黑色素瘤表型有关。我们通过分析70个具有不同水平PXDN表达的转移性黑色素瘤细胞系的转录组证实了这种关联。该分析突出了高PXDN表达与未分化侵袭性黑色素瘤表型之间的强烈关联。为了评估PXDN在黑色素瘤侵袭中的功能作用，我们在一个高侵袭性细胞系（NZM40）中敲除了PXDN。PXDN敲除使侵袭潜能降低了约50%，并降低了上皮-间质转化和侵袭标记基因的表达，这是通过RNA测序确定的，并通过蛋白质组学分析得到证实。对PXDN敲除后差异表达基因的生物信息学分析突出了与细胞外基质形成、组织和降解以及信号通路（如WNT通路）相关的基因的减少。这项研究提供了令人信服的证据，表明PXDN通过促进侵袭性、间充质样转录表型在黑色素瘤侵袭中发挥功能作用。
