<p>Wnt5a induces ROR1 and ROR2 to activate RhoA in esophageal squamous cell carcinoma cells</p>

Abstract

Background: Wnt5a is a nontransforming Wnt family member and identified as an oncogenic role on cell motility of breast cancer and glioblastoma. However, Wnt5a signaling in esophageal squamous cell carcinoma (ESCC) progression remains poorly defined. Materials and methods: Immunohistochemistry assays were used to measure the Wnt5a expression in ESCC sections. We evaluated the role of receptor tyrosine kinase-like orphan receptor (ROR)1/2 and RhoA on the invasion of ESCC cells by using cell invasion assay, immunoprecipitation, immunofluorescence, and Rho activation assay. Results: Wnt5a was highly expressed in invasive ESCC tissues compared with that in noninvasive and nonmalignant tissues. In vitro assay showed that sfrp2 (Wnt5a antagonist) largely blocked the invasion but not the colony formation of KYSE410 and KYSE520 ESCC cells. Anti-ROR1 mAb and ROR2-shRNA markedly inhibited the disheveled-associated activator of morphogenesis 1 (DAAM1) activity, RhoA activity, microfilament formation and the invasion of ESCC cells. Fluorescent phalloidin staining experiment showed ROR1/ROR2, receptors of Wnt5a signaling, and regulated the reassembly of actin filaments in ESCC cells. Further experiments showed that ROR1 was strongly associated with ROR2 in KYSE410 cells. The activation of RhoA, not Rac1 or Rac2, was involved in ROR1/ROR2 signaling pathway. By using DAAM1 shRNA, we found that RhoA was downstream of DAAM1, which could be rescued by the overexpression of wild-type DAAM1. This could be further proved by a RhoA inhibitor CCG-1423 which could inhibit the invasion of ESCC cells but not DAAM1 activity. Conclusions: Wnt5a promotes ESCC cell invasion via ROR1 and ROR2 receptors and DAAM1/RhoA signaling pathway.

<p>ANLN Directly Interacts with RhoA to Promote Doxorubicin Resistance in Breast Cancer Cells</p>

“…Many researchers have sought to determine the role of RhoA in the occurrence and development of cancers.Surveys such as that conducted by Kalpana et al show thatRhoA knockdown promotes breast cancer metastasis 28. Wnt5a promotes migration and metastasis of breast cancer and esophageal squamous cell carcinoma cells by activating RhoA 29,30. Our data verified that ANLN promoted RhoA activation by interacting with RhoA in MDA-MB-231 and MDA-MB-231/ADM cells.…”

Telomerase inhibition decreases esophageal squamous carcinoma cell migration and invasion

“…In vitro experiments confirmed that hTERT knockdown suppresses the migration and invasion abilities of ESCC cells, and suppresses the colony-formation ability of Kyse410 cells. The previous study reported that Wnt5a promotes ESCC cell invasion via retinoic acid-related orphan receptors (ROR)1 and ROR2 and disheveled-associated activator of morphogenesis 1/RhoA signaling pathway ( 60 ), thus the potential association between hTERT, Wnt5a and ROR needs to be further studied.…”

The WNT/ROR Pathway in Cancer: From Signaling to Therapeutic Intervention

“…Ligand stimulation can either induce ROR1/ROR2 homo- or heterodimerization [ 15 , 136 , 137 ], or their association with FZD receptors [ 127 , 138 , 139 ]. Moreover, in HEK293 cells, ROR2, but not ROR1, was found to form a complex with PTK7 and WNT5A, which activated JNK and AP-1 [ 140 ].…”

“…This is also true for WNT/ROR signaling [ 56 , 70 , 91 , 114 , 121 ]. Activated DVL proteins can relay the signals to distinct signaling branches centered around the small GTPases RHO, RAC and CDC42 which become activated upon WNT/ROR stimulation [ 15 , 56 , 57 , 102 , 137 ]. The regulation was even observed in vivo as a gene set enrichment analysis showed that pre-treatment CLL samples displayed a higher expression of genes associated with activation of RAC1 or RHOA than matched samples after treatment with the ROR1-blocking antibody cirmtuzumab [ 112 ].…”