22q13.31

FBLN,FIBL1

Epithelial cancers

Various cancers

Several studies have reported that fibulin-1 is overexpressed in various human neoplasias and it is implicated in processes such as invasion, motility, and in vivo tumor growth (Du et al., 2002; Greene et al., 2003; Moll et al., 2002; Qing et al., 1997; Twal et al., 2001). Fibulin-1 inhibits in vitro adhesion and motility of various carcinoma cell lines (Twal et al., 2001).

Breast cancer

Fibulin-1 was found aberrantly expressed in ~35% of 528 human primary breast cancers. Its expression is associated with improved survival in patients with lymphoid infiltrate at the tumor site (Pupa et al., 2004), suggesting a possible involvement in triggering a protective antitumor immune response. Fibulin-1 induces specific B- and T-cell-mediated responses in breast cancer patients (Forti et al., 2002; Pupa et al., 2004). Its overexpression can serve as a tool for early detection of breast cancer (Pupa et al., 2002) and acts to promote breast cancer cell survival during doxorubicin treatment (Pupa et al., 2007). In a series of 36 primary breast carcinomas, the expression of mature fibulin-1 polypeptide (100 kDa) did not correlate with estrogen receptor-alpha (ERα) or progesterone receptor (PR) levels, whereas a positive correlation was found between fibulin-1 processing (50 kDa fragment) and ERα and PR protein levels (Greene et al., 2003).

Ovarian cancer

The molecular mechanisms involved in ovarian carcinogenesis remain unclear, but growing evidence indicates that estrogens promote progression of ovarian cancer and increase expression levels of some secreted proteins. Differential overexpression of ERα versus -ERβ has been demonstrated during ovarian carcinogenesis (Clinton et al., 1996; Moll et al., 2002), suggesting that estrogen-induced proteins, including fibulin-1, may act as ovarian tumor-promoting agents. In ovarian tissues and cancer cell lines, fibulin-1C and -1D are the predominant forms, whereas fibulin-1A and -1B are weakly expressed. An increased fibulin-1C:-1D mRNA ratio in ovarian cancer cells as compared to that in normal ovaries has been observed, suggesting that the C variant is the main one involved in ovarian carcinogenesis. Fibulin-1C overexpression might provide a clue in understanding the putative role of estrogens in ERα-promoted ovarian tumor progression (Moll et al., 2002). In addition, quantitative proteomic analysis integrated with microarray data reveals that fibulin-1 is one of the ECM-related molecules important for chemotherapy response (Pan et al., 2009).

Hypermethylation of fibulin-1 gene in epithelial cancers

It has been previously reported both in gastric and prostate cancer models that Fibulin-1 acts as a tumor suppressor gene and is regulated by promoter hypermethylation (Cheng et al., 2008; Wlazlinski et al., 2007). Very recently, also in hepatocellular carcinoma (HCC) model, a downmodulation of fibulin-1 expression caused by its promoter hypermethylation has been proposed as a marker of HCC progression (Kanda et al., 2011).

Mesenchymal cancers

Recently, a distinct gene expression pattern of osteoblastic and non osteoblastic osteosarcoma groups has been proposed. In particular, they found significantly modulated the expression of several genes involved in the formation of extracellular matrix, including fibulin-1, already known to be involved in cell morphology modulation, growth and invasion of sarcoma cells (Qing et al., 1997) and suggest that fibulin-1 could be exploited as potential therapeutic target in the future (Kubista et al., 2011).

Hematological cancers

Lymphoma

Using a chemical proteomic approach in Hodgkin Lymphoma (HL), Kischel and coauthors identified several extracellular matrix proteins, including fibulin-1, overexpressed in HL (Kischel et al., 2011). Based on its high expression levels in HL biopsy samples fibulin-1 has been suggested as a potential targets for HL immunotherapy.

Synpolydactyly

Synpolydactyly is a rare genetic disorder characterized by malformations in the hands and feet, with abnormalities including increased finger and toe numbers and fusion of digits into a single digit. Molecular analysis of the reciprocal chromosomal translocation t(12;22)(p11.2;q13.3) cosegregating with a complex type of synpolydactyly indicated involvement of an alternatively spliced exon of the fibulin-1 gene (FBLN1 located in 22q13.3). Investigation of the possible functional involvement of the fibulin-1 protein in the observed phenotype showed that fibulin-1 is expressed in the ECM in association with the digits in the developing limb (Debeer et al., 2002). Thus, t(12;22) might result in haplo-insufficiency of the fibulin-1D variant, leading to the observed limb malformations.

Bernard-Soulier syndrome

Bernard-Soulier syndrome is an autosomic-dominant disease that causes alterations of the megakaryocyte/platelet lineage and is characterized by bleeding tendency, giant blood platelets and low platelet counts. An unexpected mutation in the splice acceptor site of fibulin-1 exon 19 was found in affected individuals of the Israeli Fechtner family. In all affected individuals from eight families, expression of fibulin-1 variant D was inhibited by putative antisense RNA (Lanza, 2006), raising the possibility that these autosomal-dominant giant platelet syndromes are associated with aberrant antisense gene regulation of fibulin-1.

Placenta dysplasia

Placental dysplasia is a rare human placental disorder in which the placenta is enlarged and contains cystic villi and dilated vasculature. A significant correlation was observed between fibulin-1 gene overexpression and murine placental overgrowth (Singh et al., 2006), suggesting that the gene and its product have a functional role in placenta development.

Morphogenesis of neural crest-derived structures

A significant negative correlation between fibulin-1 gene expression and some morphogenic anomalies of neural crest-derived structures in mice has been reported (Cooley et al., 2008). Such fibulin-1-deficient mice exhibit cardiac ventricular wall thinning and ventricular septal defects, with double outlet right ventricle or overriding aorta, as well as aortic arch arteries anomalies, hypoplasia of the thymus and thyroid, underdeveloped skull bones, malformations of cranial nerves and hemorrhagic blood vessels in the head and neck. The spectrum of malformations is consistent with a role for fibulin-1 in neural crest cell-dependent development of these tissues.

Acute aortic dissection

Acute aortic dissection (AAD) is a tear in the wall of the aorta that causes blood to flow between the layers of the wall of the aorta and force the layers apart. AAD is a life-threatening condition with high mortality and a mostly unclear pathophysiological mechanism. Downregulation of fibulin-1 noted in AAD compared to control samples might determine a weakening of ECM in the aorta and/or interfere with the transmission of cellular signals causing AAD (Mohamed et al., 2009).

Atherosclerotic lesions

Fibulin-1 deposits were found in association with fibrinogen in atherosclerotic lesions and in regions containing fresh thrombi. By contrast, fibulin-1 was not detected in sclerotic regions and low levels were associated with smooth muscle cells within and outside lesions (Argraves et al., 2009). Further, an accumulation of fibulin-1 deposits were found in the arterial wall and in plasma of patients with type 2 diabetes and appears to be a factor associated with arterial extracellular matrix alterations (Cangemi et al., 2011).

Thrombosis

Thrombosis, the formation of a blood clot (thrombus) inside a blood vessel, obstructs blood flow through the circulatory system. Analyses of blood plasma revealed an interaction between fibulin-1 and fibrinogen (Tran et al., 1995), pointing to potential new roles for fibulin-1 in hemostasis as well as thrombosis.

Infection disease

Streptococcus Pyogenes, which belongs to the group A of streptococcus, has been found to interact with the host fibulin 1 through its major serum opacity factor (SOF) receptor that is a major fibronectin binding protein involved in adhesion to host cells. The SOF-fibulin-1 interaction can lead to initial bacterial adhesion (Courtney et al., 2009).