Critical roles of Wnt5a–Ror2 signaling in aggressiveness of tongue squamous cell carcinoma and production of matrix metalloproteinase-2 via ΔNp63β-mediated epithelial–mesenchymal transition

Sakamoto, Toshihiro; Matsubara, Ryota; Goto, Yuichi; Jinno, Teppei; Maruse, Yasuyuki; Kaneko, Naoki; Hashiguchi, Yasuyuki; Hattori, Taichi; Tanaka, Shoichi; Kitamura, Ryoji; Kiyoshima, Tamotsu; Nakamura, Seiji

doi:10.1016/j.oraloncology.2017.03.019

Cited by 25 publications

(17 citation statements)

References 46 publications

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“…There are no other sources of information on the MMP2 regulation by WNT5A in arthritis, but in cancer cells the two types of results can be found. Several cells show induction of MMP2 by WNT5A (55,56), but others show inhibition (57). The cancer studies are also of interest because they show that WNT5A stimulates MMP2 expression through ROR2 (55,56), a receptor that was expressed at low levels in the RA FLS and that was not involved in the WNT5A modulation of migration suggesting a possible mechanism of the differential MMP2 regulation.…”

Section: Discussionmentioning

confidence: 99%

Non-Canonical WNT5A Signaling Through RYK Contributes to Aggressive Phenotype of the Rheumatoid Fibroblast-Like Synoviocytes

et al. 2020

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We hypothesized that WNT5A could contribute to the enhanced migration and invasiveness of rheumatoid arthritis fibroblast-like synoviocytes (RA FLS), which is one of the incompletely understood aspects of the RA FLS aggressive phenotype. This hypothesis is based on the previous evidence of a WNT5A role in both, RA and cell migration. Migration and invasion of RA FLS were assessed after incubation with recombinant Wnt5a (rWnt5a) or silencing of the endogenous WNT5A expression. The expression of WNT5A, WNT receptors, cytokines, chemokines, and metalloproteinases was quantified with RT-PCR. The WNT pathway was explored with gene silencing, antibody and pharmacological inhibition followed by migration assays and phosphoprotein western blots. Here, we reported that rWnt5a promoted migration and invasion of RA FLS, whereas knockdown of the endogenous WNT5A reduced them. These effects were specific to the RA FLS since they were not observed in FLS from osteoarthritis (OA) patients. Also, rWnt5a induced the expression of IL6, IL8, CCL2, CXCL5, MMP1, MMP3, MMP9, and MMP13 from baseline or potentiating the TNF induction, WNT5A signaling required the RYK receptor and was mediated through the WNT/Ca 2+ and the ROCK pathway. These pathways involved the RYK and ROCK dependent activation of the p38, ERK, AKT, and GSK3b kinases, but not the activation of JNK. Together these findings indicate that WNT5A contributes to the enhanced migration and invasiveness of RA FLS through RYK and the specific activation of ROCK and downstream kinases.

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Section: Discussionmentioning

confidence: 99%

Non-Canonical WNT5A Signaling Through RYK Contributes to Aggressive Phenotype of the Rheumatoid Fibroblast-Like Synoviocytes

et al. 2020

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“…Another potential target is ROR2, a receptor of the non-canonical Wnt pathway that is expressed specifically in HPV+ tumors. Aberrant expression of this pathway has been observed in several cancers [55–57], including tongue squamous cell carcinoma [58]. ROR2 plays a dual role in cancer, as either tumor suppressor or activator depending on the affected tissue [59].…”

Section: Discussionmentioning

confidence: 99%

Histoepigenetic analysis of HPV- and tobacco-associated head and neck cancer identifies both subtype-specific and common therapeutic targets despite divergent microenvironments

et al. 2019

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Although head and neck squamous cell carcinoma (HNSCC) has in the past been largely associated with tobacco use, human papillomavirus (HPV+) oropharynx cancer has in recent years emerged as the fastest growing type of HNSCC. Patients with HPV+ HNSCC have a better prognosis; however, the 5-year survival for both HPV+ and HPV− subtypes with recurrent or metastatic disease is poor. To gain insights into the tumor microenvironments of both HNSCC subtypes and identify potential therapeutic targets, we performed epigenomic deconvolution on 580 HNSCC samples from the TCGA dataset. Deconvolution revealed distinct molecular and histoepigenetic profiles of the two tumor subtypes, including their cellular composition, epigenomic profiles and gene expression for constituent cell types, and potential cancer cell-specific targets. Our analyses show that high abundance of both CD8 T-cells and B-cells explains better prognosis in HPV+ HNSCC. Deconvolution of gene expression profiles revealed higher expression of the immunotherapy target PD-1 in HPV+ immune cells compared to HPV− cells, suggesting that HPV+ tumors may preferentially benefit from PD-1 targeted therapy. Further analyses identified HPV+ and HPV− cancer cell surface proteins that can also serve as potential targets for therapy. Specifically, Wnt pathway receptor ROR2 is preferentially overexpressed in HPV+ subtypes, suggesting opportunities for development of targeted therapy based on HPV status. In summary, the comprehensive molecular and histoepigenetic analysis of tumor microenvironments by epigenomic deconvolution reveals potential novel biomarkers and targets for precision therapy of HNSCC.

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“…The abated adherence function contributes to the invasion and metastasis of solid tumors (19), and it is accompanied by the weakened expression of E-cadherin and reinforced expression of vimentin (17). The latest investigations demonstrated that MMPs (MMP-2, MMP-7 and MMP-9) play a significant role in EMT in tumors (20)(21)(22)(23)(24). However, the relationship between MMP-1 and EMT is still unexplored.…”

Section: Introductionmentioning

confidence: 99%

Knockdown of MMP‑1 inhibits the progression of colorectal cancer by suppressing the PI3K/Akt/c‑myc signaling pathway and EMT

Wang

Zheng

et al. 2020

Oncol Rep

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The present study aimed to investigate the role of matrix metalloproteinase-1 (MMP-1) in the development of colorectal cancer and reveal the mechanism underlying this progression. Bioinformatics methods and a public dataset were first used to analyze MMP-1 gene expression in a public dataset. MMP-1 expression in colorectal cancer patients was assessed by immunohistochemistry; its association with clinicopathological parameters and its significance for prognosis were analyzed. Then proliferation, scratch and Transwell assays and a xenograft model were used to assess the change in malignant behavior in cells transfected with an MMP-1 shRNA. Changes involved in epithelial-mesenchymal transition (EMT) and the Akt signaling pathway were detected by western blotting. According to the results, MMP-1 expression was higher in colorectal cancer tissues than it was in matched adjacent noncancerous tissues, and its high expression was significantly related to lymphatic metastasis as well as TNM stage (P<0.05). Downregulation of MMP-1 expression inhibited the progression of colorectal cancer in vitro and in vivo. Furthermore, after the cells were stably transfected with MMP-1 shRNA, the expression of N-cadherin, vimentin and Twist1 decreased while that of E-cadherin increased. The expression of p-Akt and c-Myc also decreased. In conclusion, MMP-1 may promote malignant behavior in colorectal cancer via EMT and the Akt signaling pathway.

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Critical roles of Wnt5a–Ror2 signaling in aggressiveness of tongue squamous cell carcinoma and production of matrix metalloproteinase-2 via ΔNp63β-mediated epithelial–mesenchymal transition

Abstract: Wnt5a-Ror2 signaling enhanced tongue SCC cell aggressiveness and promoted production of MMP-2 following ΔNp63β-mediated EMT.

Cited by 25 publications

References 46 publications

Non-Canonical WNT5A Signaling Through RYK Contributes to Aggressive Phenotype of the Rheumatoid Fibroblast-Like Synoviocytes

Non-Canonical WNT5A Signaling Through RYK Contributes to Aggressive Phenotype of the Rheumatoid Fibroblast-Like Synoviocytes

Histoepigenetic analysis of HPV- and tobacco-associated head and neck cancer identifies both subtype-specific and common therapeutic targets despite divergent microenvironments

Knockdown of MMP‑1 inhibits the progression of colorectal cancer by suppressing the PI3K/Akt/c‑myc signaling pathway and EMT

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