A Paradoxical Effect of Interleukin-32 Isoforms on Cancer.

Saerok Shim,Siyoung Lee,Youngmin Lee,Ho-Young Park,Tam T Nguyen,Hyunjhung Jhun,Sinae Kim,Jihyeong Hwang,Soohyun Kim,Yong-Gil Kim,Su Cheong Yeom,Sang-Yeob Kim,Yasmin Hisham,Afeisha S Taitt

doi:10.3389/fimmu.2022.837590

Abstract

IL-32 plays a contradictory role such as tumor proliferation or suppressor in cancer development depending on the cancer type. In most cancers, it was found that the high expression of IL-32 was associated with more proliferative and progression of cancer. However, studying the isoforms of IL-32 cytokine has placed its paradoxical role into a wide range of functions based on its dominant isoform and surrounding environment. IL-32β, for example, was found mostly in different types of cancer and associated with cancer expansion. This observation is legitimate since cancer exhibits some hypoxic environment and IL-32β was known to be induced under hypoxic conditions. However, IL-32θ interacts directly with protein kinase C-δ reducing NF-κB and STAT3 levels to inhibit epithelial-mesenchymal transition (EMT). This effect could explain the different functions of IL-32 isoforms in cancer. However, pro- or antitumor activity which is dependant on obesity, gender, and age as it relates to IL-32 has yet to be studied. Obesity-related IL-32 regulation indicated the role of IL-32 in cancer metabolism and inflammation. IL-32-specific direction in cancer therapy is difficult to conclude. In this review, we address that the paradoxical effect of IL-32 on cancer is attributed to the dominant isoform, cancer type, tumor microenvironment, and genetic background. IL-32 seems to have a contradictory role in cancer. However, investigating multiple IL-32 isoforms could explain this doubt and bring us closer to using them in therapy.

Highlights

The human interleukin-32 (IL-32) is a novel cytokine that exerts both pro and anti-inflammatory roles
Paradoxical effects have been reported regarding IL-32 on cancers, which may be attributed to the dominant isoform, cancer type, and genetic background
IL-32 was reported to augment cancer progression, proliferation, invasion, and metastasis in many tumors including acute myeloid leukemia (AML), hepatocellular carcinoma (HCC), and breast, lung, colon, pancreatic, and gastric cancers [5–12]

Summary

A Paradoxical Effect of Interleukin-32 Isoforms on Cancer

Saerok Shim 1†, Siyoung Lee 1,2†, Yasmin Hisham 1†, Sinae Kim 1,2, Tam T. IL-32 plays a contradictory role such as tumor proliferation or suppressor in cancer development depending on the cancer type. IL-32b, for example, was found mostly in different types of cancer and associated with cancer expansion. This observation is legitimate since cancer exhibits some hypoxic environment and IL-32b was known to be induced under hypoxic conditions. IL-32q interacts directly with protein kinase C-d reducing NF-kB and STAT3 levels to inhibit epithelial-mesenchymal transition (EMT). This effect could explain the different functions of IL-32 isoforms in cancer. We address that the paradoxical effect of IL-32 on cancer is attributed to the dominant isoform, cancer type, tumor microenvironment, and genetic background.

INTRODUCTION

Findings

CONCLUSION