Tgm3, also known as epidermal transglutaminase, is one of the pivotal enzymes responsible for the formation of protein polymers in the epidermis and the hair follicle, contributing to the protective and barrier functions of the skin and hair [5]. It has been implicated in various biological processes, potentially interacting with multiple signaling pathways, such as the PI3K/AKT pathway [2,3,4].

In hepatocellular carcinoma (HCC), Tgm3 is overexpressed compared to normal tissues, and its high expression predicts poor prognosis. Tgm3 knockdown led to decreased HCC cell proliferation, invasion, and xenograft tumour growth, inhibiting AKT, ERK, p65, and GSK3β/β-catenin activation, while promoting cleaved caspase 3 levels. It also contributed to epithelial-mesenchymal transition (EMT) in HCC [1].

In contrast, in colorectal cancer, Tgm3 expression is significantly downregulated, and it acts as a tumor suppressor, suppressing cell proliferation, invasion, and metastasis, inhibiting epithelial-to-mesenchymal transition, and activating phosphorylated AKT serine/threonine kinase [2]. Similar tumor-suppressing roles were observed in cutaneous squamous carcinoma and head and neck cancer. In cutaneous squamous carcinoma, Tgm3 inhibits tumor growth via the PI3K-AKT signaling pathway and can serve as a tumor differentiation marker [3]. In head and neck cancer, exogenous expression of Tgm3 could inhibit cell proliferation, enhance apoptosis in vitro, and suppress tumor growth in vivo [4].

In conclusion, Tgm3 plays diverse and context-dependent roles in different cancer types. In some cancers like HCC, it acts as an oncogene promoting tumorigenesis, EMT, and metastasis, while in others such as colorectal, cutaneous squamous, and head and neck cancers, it functions as a tumor suppressor. The study of Tgm3 through gene-knockout or conditional-knockout mouse models, although not explicitly detailed in the references, would further elucidate its role in these biological processes and disease conditions, providing potential therapeutic targets for cancer treatment.