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FAM83A is amplified and promotes cancer stem cell-like traits and chemoresistance in pancreatic cancer


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 FAM83Alocus 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.


Pancreatic cancer is the seventh leading cause of cancer-related mortality. 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<9 months. 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. 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%. Therefore, 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.

The intrinsic resistance of cancer stem cells (CSCs), also known as tumor-initiating cells (TICs), to conventional therapy is currently regarded as a potential therapeutic target.9 For instance, it has recently been reported that the high rates and patterns of therapeutic failure observed in ovarian cancer are closely associated with stable accumulation of drug-resistant CSCs.10 Li et al.11 found that the percentage of the CD44+CD24/low CSC sub-population, which exhibits intrinsic resistance to chemotherapy, was significantly increased in patients with breast cancer treated with chemotherapeutic drugs such as docetaxel, doxorubicin or cyclophosphamide. Similarly, CD133+ pancreatic 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, suggesting that CSCs have important roles in pancreatic cancer progression. Therefore, targeting pancreatic CSCs could potentially increase chemosensitivity and thus improve the response to treatment.

Family with sequence similarity 83, member A (FAM83A), also known as BJ-TSA-9, is located on chromosome 8q24 and was originally identified as a potential tumor-specific gene by a bioinformatics approach. Furthermore, FAM83A is overexpressed in multiple human tumors, including lung, breast, testis and bladder cancer, suggesting that FAM83A may have an oncogenic role during the development and progression of cancer. Moreover, using a 3D phenotypic reversion assay, Lee et al. identified that FAM83A may contribute to resistance to tyrosine kinase inhibitors in breast cancer through activation of the epidermal growth factor receptor/phosphatidylinositol 3 kinase/AKT signaling pathway via interacting with c-RAF and phosphatidylinositol 3 kinase p85, indicating that overexpression of FAM83A may lead to chemoresistance. Concordantly, silencingFAM83A markedly decreased the proliferation, anchorage-independent growth and invasion capabilities of breast cancer cells both in vitro and in vivo, further supporting the suggestion that FAM83A represents a potential target for cancer therapy.

Herein, we report that FAM83A is markedly overexpressed in pancreatic cancer cell lines and clinical tissues. Importantly, 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. Therefore, this study indicates FAM83A exerts a critical oncogenic role in pancreatic cancer progression and may represent a potential clinical target for cancer therapy.


Overexpression of FAM83A in pancreatic cancer is associated with poor prognosis

By analyzing a published microarray data set (NCBI/GEO/GSE16515; n=52, containing 16 non-tumor and 36 tumor samples), we found that FAM83Amessenger RNA (mRNA) was significantly upregulated in pancreatic cancer tissues compared with normal pancreatic tissues (Figure 1a). Furthermore, analysis of The Cancer Genome Atlas (TCGA) data sets revealed patients with higher FAM83Aexpression had poorer overall survival and disease-free survival (P<0.001,P<0.001; Figure 1b), suggesting that FAM83A may have a critical role in pancreatic cancer progression.

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