Brief Research Report Regional Difference in TRAF2 and TRAF3 Gene Mutations in Colon Cancers.

Seong Won Moon,Hyun Ji Son,Sug Hyung Lee,Eun Ji Choi,Nam Jin Yoo

doi:10.3389/pore.2021.625438

Seong Won Moon, Hyun Ji Son + Show 3 more

Open Access

https://doi.org/10.3389/pore.2021.625438

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Abstract

TRAF2 and TRAF3 genes of tumor necrosis factor receptor (TNF-R)-associated factor (TRAF) family are involved in diverse cell signaling, and function as both tumor suppressor gene and oncogene. Alterations of TRAF2 and TRAF3 in colon cancer (CC) along with their regional difference and microsatellite instability (MSI) are largely unknown. In the present study, we analyzed TRAF2 and TRAF3 frameshift mutations in 168 sporadic CCs (100 high MSI (MSI-H) and 68 microsatellite-stable (MSS) CCs). We identified TRAF2 and TRAF3 frameshift mutations in 4 (4%) and 3 CCs (3%) with MSI-H, respectively, but none in 68 cases of MSS CCs. Of the 168 CCs, we analyzed the mutations in multi-regions for 39 CCs (16 MSI-H and 23 MSS CCs), and discovered that 12.5% (2/16) and 6.3% (1/16) of MSI-H CCs exhibited regional difference in TRAF2 and TRAF3 mutations, respectively. In the multi-region samples of 23 MSS CCs, neither TRAF2 nor TRAF3 frameshift mutation was found. In 40% of CCs, both TRAF2 and TRAF3 expressions were increased compared to normal colon cells. Our data indicate that TRAF2 and TRAF3 frameshift mutations and their regional difference as well as altered expressions are present in MSI-H CCs, which could contribute to MSI-H cancer development.

Highlights

There are six mammalian tumor necrosis factor receptor (TNF-R)-associated factor (TRAF) family proteins that possess approximately 150 amino acid TRAF domains
We analyzed the regional difference in the TRAF2 and TRAF3 mutations in 92 regions of 16 CCs by Sanger sequencing as well as by single strand conformation polymorphism (SSCP), and no additional mutation was detected by the Sanger sequencing
We attempt to address following questions whether: 1) CCs harbor TRAF2 and TRAF3 frameshift mutations in MSIH-specific manner: 2) there is any regional difference in TRAF2 and TRAF3 frameshift mutations and 3) there are any expressional alterations of TRAF2 and TRAF3 in CCs

Summary

Introduction

There are six mammalian tumor necrosis factor receptor (TNF-R)-associated factor (TRAF) family proteins that possess approximately 150 amino acid TRAF domains. TRAFs behave as adaptor proteins for many receptors, including TNF-R, NOD-like receptors, CD40 and toll like receptor (TLR) that mediate interactions between the receptors and downstream effector molecules, including IRAKs, RIP1, RIP2, TAK1, MEKK1 and ASK1 [1,2,3,4,5]. TRAFs (TRAF2, 3, 5 and 6) work as E3 ubiquitin ligases to regulate downstream signaling [4]. TRAFs function as both adaptor protein and E3 ubiquitin ligase to regulate receptor signaling in immune responses as well as other biological processes, including immune response, cell death and survival, development, and thrombosis [4]. TRAFs are known to be involved in the pathogenesis of many human diseases, including cancers [1, 2, 5]

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