ROR2 has a protective role in melanoma by inhibiting Akt activity, cell-cycle progression, and proliferation

Abstract

Background Receptor tyrosine kinase-like orphan receptor 2 (ROR2) is a Wnt5a receptor aberrantly expressed in cancer that was shown to either suppress or promote carcinogenesis in different tumor types. Our goal was to study the role of ROR2 in melanoma. Methods Gain and loss-of-function strategies were applied to study the biological function of ROR2 in melanoma. Proliferation assays, flow cytometry, and western blotting were used to evaluate cell proliferation and changes in expression levels of cell-cycle and proliferation markers. The role of ROR2 in tumor growth was assessed in xenotransplantation experiments followed by immunohistochemistry analysis of the tumors. The role of ROR2 in melanoma patients was assessed by analysis of clinical data from the Leeds Melanoma Cohort. Results Unlike previous findings describing ROR2 as an oncogene in melanoma, we describe that ROR2 prevents tumor growth by inhibiting cell-cycle progression and the proliferation of melanoma cells. The effect of ROR2 is mediated by inhibition of Akt phosphorylation and activity which, in turn, regulates the expression, phosphorylation, and localization of major cell-cycle regulators including cyclins (A, B, D, and E), CDK1, CDK4, RB, p21, and p27. Xenotransplantation experiments demonstrated that ROR2 also reduces proliferation in vivo, resulting in inhibition of tumor growth. In agreement with these findings, a higher ROR2 level favors thin and non-ulcerated primary melanomas with reduced mitotic rate and better prognosis. Conclusion We conclude that the expression of ROR2 slows down the growth of primary tumors and contributes to prolonging melanoma survival. Our results demonstrate that ROR2 has a far more complex role than originally described.

ROR2 promotes epithelial-mesenchymal transition by hyperactivating ERK in melanoma

“…ROR2 played as a tumor promoter in non‐small cervical cancer (Sun et al 2015), renal cell carcinoma (Wright et al 2009; Yang et al 2017), colon cancer (Lara et al 2010), melanoma (O’Connell et al 2010; Castro et al 2022), and breast cancer (Henry et al 2015). In contrast, ROR2 has anti‐oncogenic functions in endometrial (Henry et al 2018), colon (Ma et al 2016), and gastric (Yan et al 2016) cancer as well as in medulloblastoma (Lee et al 2013), hepatocellular carcinoma (Nishita et al 2006) and melanoma (Castro et al 2021). The effect of ROR2 in cancer is mediated by the regulation of cell proliferation, cell migration and invasion, and in vivo tumor growth, which are modulated either positively or negatively depending on the tumor type.…”

Cucurbitacin E inhibits cellular proliferation and induces apoptosis in melanoma by suppressing HSDL2 expression

“…Activated ERK1/2 can regulate the relative proteins involved in proliferation and apoptosis, such as Bad, Bcl-2, and C-myc, thereby contributing to melanoma growth [ 25 , 26 ]. In addition, the Akt pathway is another significant pathway in melanomagenesis, promoting melanoma cell proliferation, metastasis and drug resistance, inhibiting apoptosis, and stimulating DNA mutation [ 27 , 28 ] and is associated with poor survival [ 29 ]. Therefore, our results provide the first evidence of a causal relationship between HSDL2 expression and the ERK and Akt signalling pathways in human melanoma development.…”

ROR2, a driver of “phenotype switching” in melanoma?

“…Unlike what was described in other cancers, the dual role of ROR2 in melanoma is associated with the regulation of different biological processes. We have shown that ROR2 impairs cell cycle progression and consequently inhibits the proliferation of melanoma [ 3 ]. However, ROR2 also promotes migration, epithelial to mesenchymal transition (EMT), and chemoresistance in the same cell lines [ 4 , 5 ].…”

“…In contrast, the biochemical function of ROR2, a tyrosine kinase receptor (TKR), is completely different, a fact that can be viewed as an impediment to regulating "phenotype switching". However, similar to other TKR important in melanoma such as AXL and EGFR [13], ROR2 does alter the expression of numerous proteins in melanoma [3][4][5] and other cancers [14]. Although the precise mechanism has not been completely elucidated, the signal triggered by aberrant ROR2 expression can be transduced by different signaling pathways and modulate transcription factor activity (i.e.…”