Tgm3, also known as epidermal TGM, is a pivotal enzyme responsible for the formation of protein polymers in the epidermis and hair follicle, contributing to their protective and barrier functions [5]. It is involved in processes like epidermal keratinocyte differentiation into cornified cells and the hardening of hair follicles and shafts through enzymatic cross-linking of structural proteins and keratin intermediate filaments.

In cancer research, Tgm3 shows diverse roles. In hepatocellular carcinoma (HCC), its overexpression promotes epithelial-mesenchymal transition (EMT), cell proliferation, and metastasis, predicting poor prognosis. Tgm3 knockdown decreased HCC cell proliferation, invasion, and xenograft tumour growth, and inhibited AKT, ERK, p65, and GSK3β/β-catenin activation while promoting cleaved caspase 3 levels [1].

In contrast, in colorectal cancer, cutaneous squamous carcinoma, and head and neck cancer, Tgm3 acts as a tumor suppressor. In colorectal cancer, its down-regulation is associated with tumor invasion, metastasis, and patient prognosis. Tgm3 overexpression suppressed cell proliferation, invasion, and metastasis, inhibited epithelial-to-mesenchymal transition, and activated phosphorylated AKT [2]. In cutaneous squamous carcinoma, Tgm3 expression was increased in well-differentiated tumors, and its loss was associated with poor differentiation and high recurrence. Tgm3 inhibited tumor growth via the PI3K-AKT signaling pathway [3]. In head and neck cancer, Tgm3 was down-regulated, and its exogenous expression inhibited cell proliferation, enhanced apoptosis in vitro, and suppressed tumor growth in vivo [4].

In conclusion, Tgm3 has crucial functions in epithelial differentiation. In cancer, its role varies by cancer type, either promoting or suppressing tumorigenesis. Studies using gene knockdown (a form of functional loss-of-function similar to gene knockout in concept) in different cancer cell lines and in vivo xenograft models have revealed its complex role in cancer-related biological processes, providing potential therapeutic targets for cancers such as HCC, colorectal cancer, cutaneous squamous carcinoma, and head and neck cancer.