Increased Expression of Flightless I in Cutaneous Squamous Cell Carcinoma Affects Wnt/β-Catenin Signaling Pathway.

Abstract

Cutaneous squamous cell carcinoma (cSCC) accounts for 25% of cutaneous malignancies diagnosed in Caucasian populations. Surgical removal in combination with radiation and chemotherapy are effective treatments for cSCC. Nevertheless, the aggressive metastatic forms of cSCC still have a relatively poor patient outcome. Studies have linked actin cytoskeletal dynamics and the Wnt/β-catenin signaling pathway as important modulators of cSCC pathogenesis. Previous studies have also shown that the actin-remodeling protein Flightless (Flii) is a negative regulator of cSCC. The aim of this study was to investigate if the functional effects of Flii on cSCC involve the Wnt/β-catenin signaling pathway. Flii knockdown was performed using siRNA in a human late stage aggressive metastatic cSCC cell line (MET-1) alongside analysis of Flii genetic murine models of 3-methylcholanthrene induced cSCC. Flii was increased in a MET-1 cSCC cell line and reducing Flii expression led to fewer PCNA positive cells and a concomitant reduction in cellular proliferation and symmetrical division. Knockdown of Flii led to decreased β-catenin and a decrease in the expression of the downstream effector of β-catenin signaling protein SOX9. 3-Methylcholanthrene (MCA)-induced cSCC in Flii overexpressing mice showed increased markers of cancer metastasis including talin and keratin-14 and a significant increase in SOX9 alongside a reduction in Flii associated protein (Flap-1). Taken together, this study demonstrates a role for Flii in regulating proteins involved in cSCC proliferation and tumor progression and suggests a potential role for Flii in aggressive metastatic cSCC.

• Authors: Gink N Yang, Xanthe L Strudwick, Claudine S Bonder, Zlatko Kopecki, Allison J Cowin
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 22 Issue 24 (Dec 08 2021) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 34948000 (Publication Type: Journal Article)

Chemical References

• FLII protein, human
• Microfilament Proteins
• Trans-Activators
• Methylcholanthrene

Topics

• Animals
• Carcinoma, Squamous Cell (chemically induced, genetics)
• Cell Line, Tumor
• Cell Proliferation
• Disease Models, Animal
• Female
• Gene Expression Regulation, Neoplastic
• Gene Knockdown Techniques
• Humans
• Methylcholanthrene (adverse effects)
• Mice
• Microfilament Proteins (genetics)
• Skin Neoplasms (chemically induced, genetics)
• Trans-Activators (genetics)
• Up-Regulation
• Wnt Signaling Pathway