Expression of WNT-5a and ROR2 correlates with disease severity in osteosarcoma

Abstract

Osteosarcoma, a common malignancy primarily affecting children, generally has a poor prognosis. Novel diagnostic, prognostic and therapeutic markers are required to ameliorate the negative outcomes of this disease. We investigated two potential markers, WNT-5a and ROR2, which are hypothesized to dysregulate WNT signaling pathways to promote tumorigenesis in other types of cancer. We investigated WNT-5a and ROR2 expression using immunohistochemistry in 42 osteosarcoma and 12 osteochondroma specimens, and compared the expression of these proteins with one another as well as with clinicopathological parameters. WNT-5a was detected in 34/42 (81.0%) cases and ROR2 was detected in 31/42 (73.8%) cases, significantly higher than in osteochondroma (16.7 and 25.0%, respectively; both P<0.05). Expression of these proteins was positively correlated (r=0.552, P<0.05). Furthermore, expression of WNT-5a and ROR2 was both correlated with Enneking surgical stage and tumor metastasis (P<0.05), but not with patient gender, age or pathological type. Thus, WNT-5a and ROR2 were more highly expressed in more severe disease states, and therefore may play a coordinated role in the occurrence and progression of osteosarcoma.

Knockdown of receptor tyrosine kinase-like orphan receptor 2 inhibits cell proliferation and colony formation in osteosarcoma cells by inducing arrest in cell cycle progression

“…Furthermore, Wnt/ROR2 signaling was found to promote OS cell invasion, at least in part, through the activation of a Src-family protein tyrosine kinase as well as upregulation of matrix metalloproteinase-13 expression (19,21). In addition, Lu et al (17) reported that ROR2 and Wnt5a were significantly upregulated in OS tissues, and their expression levels were correlated with Enneking surgical stage and tumor metastasis. In the current study, cyclin D1, a target gene of Wnt signaling (32), was markedly downregulated following knockdown of ROR2 in OS cells.…”

“…ROR2 acts as a tumor suppressor by inhibiting the epithelial-mesenchymal transition and tumor cell stemness through repressing Knockdown of receptor tyrosine kinase-like orphan receptor 2 inhibits cell proliferation and colony formation in osteosarcoma cells by inducing arrest in cell cycle progression β-catenin and AKT signaling (16). Recently, it has been indicated that Wnt5a/ROR2 signaling may be associated with OS severity, and plays a promotive role in the regulation of OS cell migration and invasion (17)(18)(19). However, the precise roles of ROR2 in the regulation of OS cell proliferation, as well as the underlying mechanism, have not previously been reported.…”

Deciphering signaling networks in osteosarcoma pathobiology

“…Both proteins have been found to be highly expressed in OS tissues and, in particular, elevated expression has been associated with detrimental characteristics of the tumors. 34 Furthermore, in vitro experiments have demonstrated that Wnt-5a and ROR-2 activate Src family kinases (SFKs) in order to express matrix metalloproteinase-13 (MMP-13), a molecular mechanism that ultimately leads to increased invasion in OS in a cell-autonomous manner. 35 Wnt-5a also enhances cell migration of MG-63 cells via activation of PI3K/Akt pathway.…”

LDOC1 regulates Wnt5a expression and osteosarcoma cell metastasis and is correlated with the survival of osteosarcoma patients

“…35 Many studies have reported that Wnt5a can increase the metastasis of osteosarcoma. [5][6][7][8][9][10] One study showed that Wnt5a can promote breast cancer cell migration via the Dvl2/Rab35/Rac1 signaling pathway. 36 In this study, we found that increased LDOC1 expression in osteosarcoma cells specifically decreases Wnt5a, but not Dvl2, levels.…”

“…2 The Wnt5a signaling pathway is involved in metastasis regulation in many tumor types, including osteosarcoma. [5][6][7][8][9][10] The LDOC1 (leucine zipper, down-regulated in cancer 1) protein has been shown to localize to the nucleus, and its expression is down-regulated in pancreatic and gastric cancer cells, compared to the corresponding normal human tissue. 11,12 These observations led to the hypothesis that LDOC1 functions as a tumor suppressor.…”