Absent in melanoma 2 suppresses gastric cancer cell proliferation and migration via inactivation of AKT signaling pathway

Dong Wang,Junwei Zou,Jun Dai,Zhengwu Cheng

doi:10.1038/s41598-021-87744-4

Abstract

Gastric cancer (GC) is the third leading cause of cancer-related mortality worldwide, and poses a great threat to public health. Absent in melanoma 2 (AIM2), a member of the pyrin-HIN family proteins, plays various roles across different types of cancers. However, the possible role of AIM2 in GC, as well as the underling mechanisms, are equivocal and need to be further explored. Herein, we identified that AIM2 expression was significantly down-regulated in GC tissues. Furthermore, loss of AIM2 was significantly associated with tumor size, lymph node metastasis (LNM) and tumor, node, metastases (TNM) staging, as well as poor prognosis in GC patients. Knockdown of AIM2 in GC cells significantly promoted cellular proliferation and migration, whereas AIM2 overexpression did the opposite. Mechanistically, we discovered that AIM2 regulates the AKT signaling pathway. In fact, the enhanced proliferation and migration ability induced by AIM2 knockdown was partially impaired in cells treated with the AKT inhibitor. Overall, our findings suggests that AIM2 is an independent prognostic marker and highlights a new entry point for targeting the AIM2/AKT signaling axis for GC treatment.

Highlights

Gastric cancer (GC) is the third leading cause of cancer-related mortality worldwide, and poses a great threat to public health
Immunohistochemical staining indicated that Absent in melanoma 2 (AIM2) is down-regulated in GC tumor tissues compared to normal tissues (P < 0.001; Fig. 1a,b)
AIM2 expression was further reduced in GC tissues with tumor-node-metastasis (TNM) stage III–IV (P < 0.001) and with tumor size ≥ 5 cm (P < 0.01), compared to TNM stage I–II and tumor size < 5 cm, respectively (Fig. 1d,e)

Summary

Introduction

Gastric cancer (GC) is the third leading cause of cancer-related mortality worldwide, and poses a great threat to public health. Knockdown of AIM2 in GC cells significantly promoted cellular proliferation and migration, whereas AIM2 overexpression did the opposite. In GC, AIM2 expression is reported to be significantly lower in early GC tissues compared to progressive GC tissues, and AIM2 overexpression exerts a suppressive effects on GC cell proliferation, migration and invasion[20]. We report that AIM2 expression is significantly down-regulated in GC tissues, and that reduced AIM2 expression predicts poor prognosis of GC patients. Our study demonstrates that AIM2 inhibits phosphorylation and activation of AKT, which may be responsible for the effect of AIM2 on GC cell proliferation and migration. Our data suggests that AIM2 is a novel tumor suppressor, and highlights the possible role of AIM2 as a therapeutic target for GC treatment

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