Heterozygous loss of keratinocyte TRIM16 expression increases melanocytic cell lesions and lymph node metastasis

Selina K Sutton,Chelsea Mayoh,Owen Tan,Hassina Massudi,Jessica Koach,Daniel R Carter,Belamy B Cheung,Glenn M Marshall

doi:10.1007/s00432-019-02981-5

Abstract

PurposeThe tripartite motif (TRIM)16 acts as a tumour suppressor in both squamous cell carcinoma (SCC) and melanoma. TRIM16 is known to be secreted by keratinocytes, but no studies have been reported yet to assess the relationship between TRIM16 keratinocyte expression and melanoma development.MethodsTo study the role of TRIM16 in skin cancer development, we developed a keratinocyte TRIM16-specific knockout mouse model, and used the classical two-stage skin carcinogenesis challenge method, to assess the loss of keratinocyte TRIM16 on both papilloma, SCC and melanoma development in the skin after topical carcinogen treatment.ResultsHeterozygous, but not homozygous, TRIM16 knockout mice exhibited an accelerated development of skin papillomas and melanomas, larger melanoma lesions and an increased potential for lymph node metastasis.ConclusionThis study provides the first evidence that keratinocyte loss of the putative melanoma tumour suppressor protein, TRIM16, enhances melanomagenesis. Our data also suggest that TRIM16 expression in keratinocytes is involved in cross talk between keratinocytes and melanocytes, and has a role in melanoma tumorigenesis.

Highlights

The tumour suppressive and tumour promoting effects of proteins secreted by keratinocytes on melanoma development have been previously reported
To understand the role of TRIM16 in cancer development, we developed a keratinocyte-specific TRIM16 knockout mouse model
We found that only heterozygous TRIM16+/flox knockout mice showed evidence of inguinal lymph node pigmentation which is concordant with the heterozygous TRIM16+/flox knockout mice, developing a greater number of melanoma skin lesions and squamous cell carcinoma (SCC) (Fig. 3f)

Summary

Introduction

The tumour suppressive and tumour promoting effects of proteins secreted by keratinocytes on melanoma development have been previously reported These include the increased expression and paracrine secretion of maspin by Selina K. The tripartite motif-containing (TRIM) proteins family is functionally diverse and involved in cellular processes including cell cycle regulation, proliferation, differentiation, ubiquitination, apoptosis, tumour suppress functions and oncogenesis(Sardiello et al 2008). Additional work has demonstrated that TRIM16 inhibits neuroblastoma cell proliferation through cell cycle regulation and localization to the nucleus (Bell et al 2013). Cell cycle progression is attenuated through changes in cyclin D1 and p27 These data implicate TRIM16 as a regulator of G1/S progression and cellular differentiation (Bell et al 2013). TRIM16 has been shown to restore retinoid sensitivity to retinoid-resistant breast and lung cancer cells via epigenetic mechanism of histone acetylation and restoration of RARβ2 transcription (Raif et al 2009)

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