Background: Dysregulation of ubiquitin ligases plays a crucial role in the development and progression of various human tumors. F-box only protein 22 (FBXO22), an F-box E3 ubiquitin ligase, has been reported to participate in diverse aspects of cancer progression. However, the clinical significance and biological function of FBXO22 in pancreatic cancer remain poorly understood.
Aims: This study aimed to investigate the role of FBXO22 in promoting pancreatic cancer growth.
Methods: FBXO22 expression was detected in pancreatic cancer and adjacent normal tissues using qRT-PCR, western blotting, and immunohistochemistry. Ectopic expression and knockdown of FBXO22 were performed to measure the impact on pancreatic cancer cells growth by CCK-8, colony formation, and tumorigenicity assay. Bioinformatics analysis uncovered the potential correlation between FBXO22 and various signaling pathways. Western blotting and immunoprecipitation were performed to identify FBXO22-interacting proteins.
Results: We observed that FBXO22 was upregulated in samples obtained from patients with pancreatic cancer compared with its levels in the adjacent normal tissues, and an elevated FBXO22 level was obviously associated with poor prognosis among patients with pancreatic cancer. FBXO22 knockdown impaired pancreatic cancer cell growth both in vitro and in vivo, whereas FBXO22 overexpression accelerated pancreatic cancer cell growth. Furthermore, we found that FBXO22 contributed to pancreatic cancer cell growth by deactivating the Hippo pathway. Mechanistically, FBXO22 directly interacts with and destabilizes the large tumor suppressor 2 (LATS2), which is a critical regulator of the Hippo pathway. Blocking LATS2 leads to the loss of FBXO22-mediated oncogenic effect in pancreatic cancer.
Conclusions: These findings provide new insights into the upstream regulation of the Hippo pathway inactivation in pancreatic cancer growth and identify FBXO22 as a potential therapeutic target for this lethal malignant tumor.
Keywords: FBXO22; Hippo pathway; LATS2; Pancreatic cancer; Ubiquitination.
© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.