BJ-TSA-9, a Novel Human Tumor-Specific Gene, Has Potential as a Biomarker of Lung Cancer

Li, Yunyan; Dong, Xiao-yuan; Yin, Yuqin; Su, Yan-Rong; Xu, Qiantong; Zhang, Yuxia; Pang, Xuewen; Zhang, Yu; Chen, Weifeng

doi:10.1593/neo.05406

Cited by 71 publications

(58 citation statements)

References 30 publications

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“…In all 3 cell lines, expression of a shRNA targeting FAM83B resulted in decreased FAM83B expression, growth, and AIG compared with control cells expressing a shRNA targeting GFP (Supplemental Figure 16 and Figure 8, H and I). Taken together, our data suggest that tumors has been identified as a lung cancer biomarker, reported to be elevated in approximately 70% of lung adenocarcinomas (17). In addition, FAM83A is overexpressed in breast cancer, is associated with poor prognosis, activates MAPK and PI3K-AKT signaling, and confers decreased sensitivity to EGFR-TKIs (9).…”

Section: Figurementioning

confidence: 54%

FAM83B mediates EGFR- and RAS-driven oncogenic transformation

et al. 2012

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Aberrant regulation of growth signaling is a hallmark of cancer development that often occurs through the constitutive activation of growth factor receptors or their downstream effectors. Using validation-based insertional mutagenesis (VBIM), we identified family with sequence similarity 83, member B (FAM83B), based on its ability to substitute for RAS in the transformation of immortalized human mammary epithelial cells (HMECs). We found that FAM83B coprecipitated with a downstream effector of RAS, CRAF. Binding of FAM83B with CRAF disrupted CRAF/14-3-3 interactions and increased CRAF membrane localization, resulting in elevated MAPK and mammalian target of rapamycin (mTOR) signaling. Ablation of FAM83B inhibited the proliferation and malignant phenotype of tumor-derived cells or RAS-transformed HMECs, implicating FAM83B as a key intermediary in EGFR/RAS/MAPK signaling. Analysis of human tumor specimens revealed that FAM83B expression was significantly elevated in cancer and was associated with specific cancer subtypes, increased tumor grade, and decreased overall survival. Cumulatively, these results suggest that FAM83B is an oncogene and potentially represents a new target for therapeutic intervention. IntroductionThe discovery of targets suitable for the development of specific and effective anticancer therapies remains one of the principal challenges facing cancer research. The identification of genes involved in tumorigenesis is essential for devising new targeted therapeutics and can be greatly facilitated by phenotypic-based forward genetic screens for mutations contributing to malignant transformation in human cell models. We recently created a validation-based insertional mutagenesis (VBIM) strategy that expands the application of reversible promoter insertion to nearly any type of mammalian cell (1). The VBIM strategy uses the unique transcriptomes of different human epithelial cell types and provides opportunities for the identification of tissue-specific oncogenes and tumor suppressors. The VBIM lentiviruses alter the unique transcriptome of the model system by introducing promoters into the genome, resulting in dominant genetic alterations that increase the expression of sequences neighboring the insertion sites. By using Cre recombinase-mediated excision of the VBIM promoter, one can revert the VBIM-specific mutants and distinguish them from spontaneous mutants, allowing spontaneous mutants to be eliminated from further study.We have used the VBIM strategy to identify family with sequence similarity 83, member B (FAM83B), as a putative oncogene capable of promoting the transformation of immortalized human mammary epithelial cells (HMECs). We demonstrated that elevated FAM83B expression stimulated aberrant activation of MAPK signaling by altering binding of regulatory 14-3-3 proteins to CRAF and increasing CRAF membrane localization. In addition to driving cellular transformation, FAM83B mRNA was significantly elevated in many human tumor tissues. Ablation of FAM83B from breast cancer cells with ele...

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Section: Figurementioning

confidence: 54%

FAM83B mediates EGFR- and RAS-driven oncogenic transformation

et al. 2012

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“…FAM83A was amplified in a number of subtypes of lung cancer (Supplemental Figure 8A and refs. 16,34). Lung cancers that were resistant to gefitinib treatment were found to have higher FAM83A expression than the sensitive cancers (Supplemental Figure 8B, Supplemental Table 2 We have reported previously that EGFR-TKI-mediated reversion of T4-2 cells suppresses the downstream MAPK pathway (12,14,15).…”

Section: Figurementioning

confidence: 84%

FAM83A confers EGFR-TKI resistance in breast cancer cells and in mice

Lee¹,

Meier²,

Furuta³

et al. 2012

J. Clin. Invest.

121

187

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Breast cancers commonly become resistant to EGFR-tyrosine kinase inhibitors (EGFR-TKIs); however, the mechanisms of this resistance remain largely unknown. We hypothesized that resistance may originate, at least in part, from molecular alterations that activate signaling downstream of EGFR. Using a screen to measure reversion of malignant cells into phenotypically nonmalignant cells in 3D gels, we identified FAM83A as a candidate cancer-associated gene capable of conferring resistance to EGFR-TKIs. FAM83A overexpression in cancer cells increased proliferation and invasion and imparted EGFR-TKI resistance both in cultured cells and in animals. Tumor cells that survived EGFR-TKI treatment in vivo had upregulated FAM83A levels. Additionally, FAM83A overexpression dramatically increased the number and size of transformed foci in cultured cells and anchorage-independent growth in soft agar. Conversely, FAM83A depletion in cancer cells caused reversion of the malignant phenotype, delayed tumor growth in mice, and rendered cells more sensitive to EGFR-TKI. Analyses of published clinical data revealed a correlation between high FAM83A expression and breast cancer patients' poor prognosis. We found that FAM83A interacted with and caused phosphorylation of c-RAF and PI3K p85, upstream of MAPK and downstream of EGFR. These data provide an additional mechanism by which tumor cells can become EGFR-TKI resistant.

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“…SFN has been reported to be overexpressed in early invasive lung adenocarcinoma (Shiba-Ishii et al, 2011). FAM83A, also known as tumor antigen BJ-TSA-9, is a potential biomarker in lung cancer (Li et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Genome-scale meta-analysis of DNA methylation during progression of lung adenocarcinoma

Qh¹,

Xh²,

Zm³

et al. 2015

Genet. Mol. Res.

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ABSTRACT. Identification of epigenetic alterations in tumors has become a common method for identifying genes critical to cancer development and progression. Thus, we identified DNA methylation alterations on the genome scale during lung adenocarcinoma (LADC) progression to understand the carcinogenic process and identify clinically relevant biomarkers. We found that epigenetic alterations in LADC mainly occur during the early stage of LADC progression, and there are no significant methylation differences between early-stage and late-stage LADCs. This suggests that DNA methylation alterations characterize a turning point of early events in LADC progression. By comparing DNA methylation between early-stage LADCs and normal lung tissues, we further identified 940 genes with significant alterations in DNA methylation. Sixty-seven genes were found to exhibit strong correlation between methylation alterations and expression changes, based on associated gene expression data. According to gene ontology analysis, these genes are involved in lung development, respiratory 9200-9214 (2015) system development, cell cycle, histidine metabolism, the Wnt signaling pathway, and the p53 signaling pathway. We also found that genes on chromosome 18 most frequently showed promoter hypermethylation. Moreover, we found that LADC-associated DNA hypomethylation occurred preferentially at neither histone H3 lysine 4 nor histone H3 lysine 27 mark domains in human embryonic stem cells (NMDs) and that hypomethylation of NMDs was associated with a poor prognostic signature in LADC. Our findings have important implications for LADC progression because of the identification of novel epigenetic biomarkers potentially involved in early-stage LADC and for establishing the importance of NMD DNA hypomethylation for predicting prognosis in LADC.

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BJ-TSA-9, a Novel Human Tumor-Specific Gene, Has Potential as a Biomarker of Lung Cancer

Cited by 71 publications

References 30 publications

FAM83B mediates EGFR- and RAS-driven oncogenic transformation

FAM83B mediates EGFR- and RAS-driven oncogenic transformation

FAM83A confers EGFR-TKI resistance in breast cancer cells and in mice

Genome-scale meta-analysis of DNA methylation during progression of lung adenocarcinoma

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