11q13.1

FRA,FRA1,fra-1

Thyroid cancer

Analysis of samples from thyroid cancer patients has shown an increase in Fra-1 protein expression in thyroid nodules (Chiappetta et al., 2000). Induction of Fra-1 expression has also been observed in human thyroid cancer cell lines (Battista et al., 1998). Inhibition of Fra-1 prevents the retrovirally induced neoplastic transformation of rat thyroid cells (Vallone et al., 1997). In thyroid cancer cells, Fra-1 binds to the cyclin A promoter and regulates its expression during cell-cycle progression (Casalino et al., 2007).

Non-small-cell lung cancer (NSCLC)

Expression of AP-1 family proteins, and particularly Fra-1 has been detected in NSCLC cell lines (Risse-Hackl et al., 1998). Decreased levels of Fra-1 protein expression have been noted in the tumor tissue of non small cell lung cancer patients (Ma et al., 2009), and these decreased levels have been positively correlated with progression of tumor stage and worsening prognosis. Ectopic expression of Fra-1 in lung adenocarcinoma cells induces cancer. Interestingly, it has been reported that a DNA vaccine specific to Fra-1 prevents pulmonary cancer metastasis in syngeneic mice (Luo et al., 2005).

Breast cancer

Increased expression of Fra-1 was observed in human breast cancer cells (Philips et al., 1998). Several studies have shown its involvement in cancer cell proliferation, motility and invasiveness (Bamberger et al., 1999; Belguise et al., 2005; Logullo et al., 2011). An increase in nuclear or cytoplasmic localization of Fra-1 has been considered as a marker of progression of breast cancer (Song et al., 2006, Chiappetta et al., 2007). Knockdown of Fra-1 in tumor associated macrophages with small interfering RNA has been found to significantly suppress the invasion, angiogenesis and metastasis of breast cancer tumor cells (Luo et al., 2010). Likewise, knockdown of Fra-1 in estrogen- resistant MCF-7 cells significantly affected their growth and enhanced their susceptibility to cell death in response to estrogen treatment (Pennanen et al., 2011). An increased accumulation of Fra-1 protein in estrogen-negative breast cancer cells is mediated through PKCθ pathway (Belguise et al., 2012). A mouse Fra-1 targeted DNA vaccine has been found to be effective in protection against breast cancer in mice (Luo et al., 2003). Low level of miRNA-34 has been correlated with an elevated level of Fra-1 expression in breast cancer tissues and cell lines, but ectopic miRNA-34 expression causes a down-regulation of Fra-1 levels and inhibits breast cancer cell progression (Yang et al., 2012). In a different study, Fra-1 overexpression was shown to increase the chemosensitive of breast cancer stem cells, suggesting Fra-1 can be considered as a prognostic responsive marker in breast cancer therapy (Lu et al., 2012).

Bladder cancer

An increased level of Fra-1 expression is found in bladder tumor and cancer cell lines. Fra-1, via the transcriptional induction of the receptor tyrosine kinase AXL, promotes bladder cancer cell motility (Sayan et al., 2012).

Colon cancer

Fra-1 and its dimeric partner, c-Jun, are up-regulated in human colorectal tumors (Zhang et al., 2005; Wang et al., 2002). In colon carcinoma cells, the basal induction and stabilization of Fra-1 has been shown to be regulated by ERK activity, and knockdown of Fra-1 suppresses colon cancer cell polarization and progression (Vial and Marshall, 2003). A potential role for Fra-1 in the regulation of vimentin during Ha-RAS-induced epithelial-to- mesenchymal transition and migration has been documented (Andreolas et al., 2008). By upregulating miR-34a, p53 indirectly down regulates Fra-1 mRNA and protein expression in colon cancer cells and inhibits cell migration and invasion (Wu et al., 2012).

Prostate cancer

Akt signaling contributes to Fra-1 induction in the prostate cancer cells, mainly at the transcription level (Tiwari et al., 2003). An abnormal activation of Fra-1 has been linked to elevated expression levels of IL-6, which promote prostate cancer cell progression and resistance to chemotherapeutic agents (Zerbini et al., 2003).

Esophageal squamous cell carcinoma (ESCC)

Immunoreactive analysis of two different ESCC cell lines (HKESC-1 and HKESC-2) derived from ESCC patients has demonstrated Fra-1 expression in these cell line (Hu et al., 2001). An elevated level of Fra-1expression is associated with poor prognosis of ESCC. Furthermore, Fra-1 knockdown in ESCC cell lines decreases tumor cell progression and invasion (Usui et al., 2012).

Nasopharyngeal carcinoma (NPC)

Expression profiling of nasopharyngeal carcinoma and normal cells has revealed elevated expression levels of Fra-1 in NPC cancer cells (Fung et al., 2000). Fra-1 has been shown to play an important role in controlling latent membrane protein 2A (LMP2A)-induced NPC epithelial cell motility and invasiveness (Lan et al., 2012). Either inhibition of Fra-1 induction or suppression of ERK1 and ERK2 activation will block the LMP2A-induced MMP-9 expression required for cancer cell progression.

Glioma

Ectopic Fra-1 expression in malignant glioma cells leads to phenotypic changes associated with invasiveness and tumorigenicity (Debinski and Gibo, 2005). In contrast, knock down of Fra-1 in high-grade glioma (HGG) cells alters the morphology, reduces both anchorage-independence and tumorigenic potential (Debinski and Gibo, 2011). In rat C6 glioma cells, Fra-1 overexpression suppresses their proliferation rate and tumorogenic potential and promotes cellular apoptosis (Shirsat and Shaikh., 2003).

Head and neck squamous cell carcinoma (HNSCC)

Analysis of the tumor samples from patients with head and neck squamous cell carcinomas (HNSCC) has shown an increase in Fra-1 mRNA expression when compared to matched adjacent mucosa samples. Furthermore, tumor tissue staining for Fra-1 in tumor tissues is intensely more reactive immunoreactive than that of adjacent normal tissue (Mangone et al., 2005).

Fibrosis

Fra-1 transgenic mice have been shown to be prone to developing biliary hepatic fibrosis, and Fra-1 has been associated with ductular proliferation and infiltration of inflammatory cells (Kireva et al., 2011). On the other hand, it negatively regulates pulmonary fibrosis (Rajasekaran et al., 2012). Genetic disruption of Fra-1 causes increased levels of inflammation, collagen accumulation, and profibrotic and fibrotic gene expression following bleomycin treatment when compared to wild-type Fra-1.

Osteopetrosis

Genetic disruption of Fos leads to osteopetrosis in mice (Matsuo et al., 2000). However, over expression of Fra-1 rescues this phenotype in c-Fos mutant mice. Rankl, an osteoclast differentiation factor, has been reported to induce Fra-1 expression in a c-Fos-dependent manner, suggesting the involvement of c-Fos-RANKL-Fra-1 signaling in osteoclast differentiation. It has also been reported that overexpression of Fra-1 in mice increases bone mass up to 5-fold compared to wild-type mice (Roschger et al., 2004).

Acute lung injury and Sepsis

Increased expression of Fra-1 has been reported in lung epithelial cell of acute respiratory syndrome patients (Fudala et al., 2011). Mice lacking Fra-1 show decreased levels of acute lung injury and inflammation as well as increased survival following endotoxin (LPS) treatment when compared to their wild-type counterparts (Vaz et al., 2012); this improvement was associated with diminished and increased levels of NF-kB and c-Jun/AP-1 binding, respectively. In agreement with this result, mice overexpressing Fra-1 were shown in another study to have enhanced susceptibility to endotoxin-induced death (Takada et al., 2011).