Abstract
Cancer stem cells (CSCs), also known as tumor-initiating cells (TICs), contribute to tumorigenesis, resistance to chemoradiotherapy and recurrence in human cancers, suggesting targeting CSCs may represent a potential therapeutic strategy. In the current study, we found family with sequence similarity 83, member A (FAM83A) is significantly overexpressed and associated with poorer overall survival and disease-free survival in pancreatic cancer. Overexpression of FAM83A markedly promoted, whereas inhibition of FAM83A decreased, CSC-like traits and chemoresistance both in vitro and in an in vivo mouse model of pancreatic cancer. Furthermore, overexpression of FAM83A activated the well-characterized CSC-associated pathways transforming growth factor-β (TGF-β) signaling and Wnt/β-catenin signaling. Importantly, the FAM83A locus was amplified in a number of human cancers and silencing FAM83A in associated cancer cell lines inhibited activation of the WNT/β-catenin and TGF-β signaling pathways and reduced tumorigenicity. Taken together, these results indicate that FAM83A has a vital oncogenic role to promote pancreatic cancer progression and may represent a potential clinical target.
Highlights
The findings of the present study provide new insight into a potential oncogenic role for FAM83A in pancreatic cancer progression and highlight the ability of FAM83A to promote pancreatic cancer stem cells (CSCs)-like traits
We demonstrate FAM83A is significantly overexpressed in pancreatic cancer and promotes CSC-like traits by activating the Wnt/β-catenin and transforming growth factor-β (TGF-β) pathways
Our results uncover a novel mechanism leading to overexpression of FAM83A in pancreatic cancer, and suggest this protein has potential as a therapeutic target for pancreatic cancer
Summary
Pancreatic cancer is the seventh leading cause of cancer-related mortality.[1,2] Despite advances in modern medical technology, pancreatic cancer has benefited from marginal improvements in survival outcomes; the 5-year overall survival rate of patients with pancreatic cancer is only 6% and the median survival time is o9 months.[3,4] Failure of conventional chemotherapy, including both intrinsic and acquired chemoresistant behavior, is a major factor that significantly decreases the clinical efficacy of chemotherapy for pancreatic cancer.[5,6] The response rates to common chemotherapeutic drugs, such as gemcitabine, erlotinib and 5-fluorouracil (5-FU), in pancreatic cancer have been reported to be lower than 25%.5,7,8 better understanding the molecular mechanisms that underlie drug resistance in pancreatic cancer could lead to the development novel therapeutic strategies for this highly lethal malignancy. CSCs have been demonstrated to be exclusively tumorigenic and highly resistant to chemotherapy and radiation therapy, and the CD133+ CXCR4+ sub-population of pancreatic CSCs is critical for tumor metastasis,[12,13,14] suggesting that CSCs have important roles in pancreatic cancer progression. Silencing FAM83A markedly decreased the proliferation, anchorage-independent growth and invasion capabilities of breast cancer cells both in vitro and in vivo,[19] further supporting the suggestion that FAM83A represents a potential target for cancer therapy. Silencing FAM83A markedly decreased pancreatic CSC-like traits in vitro and tumorigenicity in vivo via inhibition of two well-established CSC-associated signaling pathways, transforming growth factor-β (TGF-β) and Wnt/β-catenin. This study indicates FAM83A exerts a critical oncogenic role in pancreatic cancer progression and may represent a potential clinical target for cancer therapy. Hospital of Sun Yat-Sen University, No 600 Tianhe Road, Guangzhou 510630, China
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