Operative ubiquitin-specific protease 22 deubiquitination confers a more invasive phenotype to cholangiocarcinoma

Abstract

Oncogenic ubiquitin-specific protease 22 (USP22) is implicated in a variety of tumours; however, evidence of its role and underlying molecular mechanisms in cholangiocarcinoma (CCA) development remains unknown. We collected paired tumour and adjacent non-tumour tissues from 57 intrahepatic CCA (iCCA) patients and evaluated levels of the USP22 gene and protein by qPCR and immunohistochemistry. Both the mRNA and protein were significantly upregulated, correlated with the malignant invasion and worse OS of iCCA. In cell cultures, USP22 overexpression increased CCA cell proliferation and mobility, and induced epithelial-to-mesenchymal transition (EMT). Upon an interaction, USP22 deubiquitinated and stabilized sirtuin-1 (SIRT1), in conjunction with Akt/ERK activation. In implantation xenografts, USP22 overexpression stimulated tumour growth and metastasis to the lungs of mice. Conversely, the knockdown by USP22 shRNA attenuated the tumour growth and invasiveness in vitro and in vivo. Furthermore, SIRT1 overexpression reversed the USP22 functional deficiency, while the knockdown acetylated TGF-β-activated kinase 1 (TAK1) and Akt. Our present study defines USP22 as a poor prognostic predictor in iCCA that cooperates with SIRT1 and facilitates tumour development.

USP22 regulates lipidome accumulation by stabilizing PPARγ in hepatocellular carcinoma

“…Our study found that USP22 might act upstream of p-AKT(S473), however with or without serum incubation USP22 still upregulates PPARγ expression. Therefore USP22 stabilizes PPARγ may independently from AKT activation, and this implies that USP22 involves multiple regulation pathways 45 . Importantly, previous study has clarified that AKT pathway is significantly activated in HCC patients 46 .…”

miR-99b/let-7e/miR-125a cluster suppresses pancreatic cancer through regulation of NR6A1

“…Pancreatic cancer (PCa), known for its high malignancy, poses formidable challenges in treatment and prognosis, primarily due to its propensity for aggressive invasion and metastasis [1]. Clinically, many patients with PCa, are often accompanied by elevated levels of alkaline phosphatase and circulating bilirubin [2][3][4].…”

“…Furthermore, miR-125a, belonging to the miR-10 family, has been shown to foster resistance to gemcitabine in PCa cells by targeting A20 [14]. miR-125a belongs to the miR-10 family, which includes two homologs (hsa-miR-125b-1, Am J Cancer Res 2024;14 (1):114-129 hsa-miR-125b-2) that play key roles in various molecular and cellular processes, such as differentiation, proliferation, apoptosis, and regulation of matrix metalloproteinases [15]. let-7 was first identified in 2000 and is the second miRNA identified after lin-4, which has 13 family members with the same sequence homology in the seed region, most of which are associated with the regulation of cancer drug sensitivity [16].…”