AIM2 Inhibits BRAF-Mutant Colorectal Cancer Growth in a Caspase-1-Dependent Manner.

Shailendra Shah,Yizhou Huang,Ran Jing,Huimin Chen,Yang Luo,Jianjun Chen,Jay N. Shah,Ming Zhong,Shaolan Qin

doi:10.3389/fcell.2021.588278

Abstract

Absent in melanoma 2 (AIM2), a DNA sensor that plays an important role in natural immunity system, has been reported to participate in colorectal cancer (CRC) development. However, the functional role of AIM2 in BRAF-mutant CRC remains unclear. In this study, we first investigated AIM2 expression level in BRAF-mutant CRC tumor tissues. Overexpression of AIM2 in CRC cells was performed to investigate the effect of AIM2 on CRC cell viability, and cell death detection and caspase activity assay were performed to explore the mechanism that AIM2 impacts the growth of BRAF-mutant CRC cells. Moreover, we confirmed the antitumor effect of AIM2 in BRAF-mutant CRC cell-derived tumor xenograft (CDX) models as well as patient-derived organoids (PDOs). Herein, we reported that AIM2 expression was lower in BRAF-mutant than that in BRAF wild-type CRC tumor tissues. Restoring the expression of AIM2 in BRAF-mutant CRC cells greatly inhibits the tumor cell growth by inducing necrotic cell death. Mechanism studies revealed that AIM2-induced cell death is in a caspase-1-dependent manner. Additionally, overexpression of AIM2 significantly inhibits tumor growth and metastasis in BRAF-mutant CRC in vivo, which was further confirmed in BRAF-mutant CRC PDOs. Taken together, our data suggested that AIM2 inhibits BRAF-mutant colon cancer growth in a caspase-1-dependent manner, which may provide evidence to understand the pathogenesis of CRC with BRAF-mutant, as well as new strategies for manipulation of CRC.

Highlights

Colorectal cancer (CRC) is one of the most common malignant tumors in humans, resulting in more than 600,000 deaths per year, which accounts for approximately 10% of all cancer-related deaths in the world (Brenner et al, 2014; Bray et al, 2018)
We found that the expression level of Absent in melanoma 2 (AIM2) was significantly lower in colorectal cancer (CRC) with BRAF mutation compared with that of CRC without BRAF mutation
We found that AIM2 induces BRAF-mutant CRC cell death in a caspase-1-dependent manner

Summary

Introduction

Colorectal cancer (CRC) is one of the most common malignant tumors in humans, resulting in more than 600,000 deaths per year, which accounts for approximately 10% of all cancer-related deaths in the world (Brenner et al, 2014; Bray et al, 2018). BRAF mutation is frequently occurred in CRC, with ∼10% of CRCs harboring a missense mutation at codon 600 (V600E; Cancer Genome Atlas Network, 2012). This mutation results in activating BRAF function and constitutively activates mitogen-activated protein kinase signaling (Wan et al, 2004). CRC tumors with this type of BRAF-mutant form a distinct molecular subtype with high progression and poor prognosis (Roth et al, 2010; Yaeger et al, 2014). Despite much advancement in diagnosis and treatment for this disease, the prognosis of BRAF-mutant CRC patients is still very poor because of AIM2 in Colorectal Cancer obstinate recurrence and distant metastasis (Eefsen et al, 2015; Malik et al, 2015).

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