title: Demonstration of a WNT5A-IL-6 positive feedback loop in melanoma cells: Dual interference of this loop more effectively impairs melanoma cell invasion.
abstract: Increased expression and signalling of WNT5A and interleukin-6 (IL-6) have both been shown to promote melanoma progression. Here, we investigated the proposed existence of a WNT5A-IL-6 positive feedback loop that drives melanoma migration and invasion. First, the HOPP algorithm revealed that the invasive phenotype of cultured melanoma cells was significantly correlated with increased expression of WNT5A or IL-6. In three invasive melanoma cell lines, endogenous WNT5A protein expression was related to IL-6 protein secretion. Knockdown with anti-IL-6 siRNAs or treating WM852 melanoma cells with a neutralising anti-IL-6 antibody reduced WNT5A protein expression. Conversely, the silencing of WNT5A expression by WNT5A siRNAs or treating WM852 melanoma cells with Box5 (a WNT5A antagonist) significantly reduced IL-6 secretion. Interestingly, these effects occurred at the protein level but not at the transcriptional levels. Functionally, we demonstrated that combined siRNA knockdown of WNT5A and IL-6 expression or the simultaneous inhibition of WNT5A and IL-6 signalling inhibited melanoma cell invasion more effectively than suppressing each factor individually. Together, our results demonstrate that WNT5A and IL-6 are connected through a positive feedback loop in melanoma cells and that the combined targeting of both molecules could serve as an effective therapeutic means to reduce melanoma metastasis.
authors.affiliation: Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Clinical Research Centre, Skåne University Hospital, SE-20502 Malmö, Sweden.
authors.forename: Rickard
authors.initials: R
authors.lastname: Linnskog
authors.affiliation: Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Clinical Research Centre, Skåne University Hospital, SE-20502 Malmö, Sweden.
authors.forename: Purusottam
authors.initials: P
authors.lastname: Mohapatra
authors.affiliation: Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Clinical Research Centre, Skåne University Hospital, SE-20502 Malmö, Sweden.
authors.forename: Farnaz
authors.initials: F
authors.lastname: Moradi
authors.affiliation: Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Clinical Research Centre, Skåne University Hospital, SE-20502 Malmö, Sweden.
authors.forename: Chandra Prakash
authors.initials: CP
authors.lastname: Prasad
authors.affiliation: Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Clinical Research Centre, Skåne University Hospital, SE-20502 Malmö, Sweden.
authors.forename: Tommy
authors.initials: T
authors.lastname: Andersson
mesh_terms: D000465:Algorithms; D045744:Cell Line, Tumor; D002465:Cell Movement; D025461:Feedback, Physiological; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D008545:Melanoma / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D034741:RNA, Small Interfering / Q000378:metabolism; D012878:Skin Neoplasms / Q000378:metabolism*; D000071818:Wnt-5a Protein / Q000378:metabolism*
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; D034741:RNA, Small Interfering; C085389:WNT5A protein, human; D000071818:Wnt-5a Protein
keywords: Box5; WNT5A; anti-IL-6-Ab; interleukin-6; melanoma invasion