Silencing Filamin A Inhibits the Invasion and Migration of Breast Cancer Cells by Up-regulating 14-3-3σ

Filamin A and 14-3-3-σ are closely associated with the development of breast cancer. However, the exact relationship between them is still unknown. The present study aimed to examine the interaction of filamin A with 14-3-3-σ in the invasion and migration of breast cancer. RNA interference technology was employed to silence filamin A in MDA-MB-231 cells. Real-time PCR and Westem blotting were used to detect the expression of filamin A and 14-3-3-σ at mRNA and protein levels, respectively. Double immunofluorescence was applied to show their colocalization morphologically. Wound healing assay and Trans-well assay were used to testify the migration and invasion of MDA-MB-231 cells in filamin A-silenced cells. The results showed that silencing filamin A significantly increased the mRNA and protein levels of 14-3-3σ. In addition, double immunofluorescence displayed that filamin A and 14-3-3σ were predominantly colocalized in the cytoplasm of MDA-MB-231 cells. Silencing filamin A led to the enhanced fluorescence of 14-3-3σ. Furthermore, cell functional experiments showed that silencing filamin A inhibited the migration and invasion of MDA-MB-231 cells in vitro. In conclusion, silencing filamin A may inhibit the invasion and migration of breast cancer cells by upregulating 14-3-3σ.

New cancer suppressor gene for colorectal adenocarcinoma:Filamin A

AIM:To determine the expression and significance of filamin A(FLNa)in colorectal adenocarcinoma tissue.METHODS:The expression of FLNa in 46 colorectal cancer tissues and normal tissues was detected by immunohistochemistry,reverse transcription polymerase chain reaction(RT-PCR)and Western blotting,and its relationship with clinical parameters and prognosis was analyzed.RESULTS:The positive expression of FLNa in cancer tissues was lower than that in normal mucosa,and the difference was statistically significant.The expression of FLNa correlated with liver metastasis,lymph node metastasis and rectal invasion depth,regardless of sex,age,tumor location,tumor size,gross shape and histological type of colorectal carcinoma.Multivariate analysis showed that FLNa was an independent risk factor for postoperative survival of patients with colorectal adenocarcinoma.Moreover,survival analysis showed that the expression level of FLNa was closely related with survival of patients with colorectal adenocarcinoma.The results of RT-PCR and Western blotting were consistent with those of immunohistochemistry.CONCLUSION:FLNa showed low expression in colorectal adenocarcinoma,high correlation with the incidence and development of colorectal cancer,and was considered an indicator of prognosis.

Filamin A Gene Associated Periventricular Nodular eterotopia and Epilepsy in a Cohort of Chinese Patients

Periventricular nodular heterotopia （PNH） is a cortical malformation commonly found in epilepsy patients caused by the failure of neurons to migrate.Patients with PNH present with various clinical manifestations and genetic mutations. Despite their remarkable structural malformations, PNH patients generally have no neurological deficits or cognitive disabilities. However, particularly in patients with abnormal cortical development, the systematic abnormalities can also be severely delayed.

Rare loss-of-function variants in FLNB cause non-syndromic orofacial clefts

Orofacial clefts (OFCs) are the most common congenital craniofacial disorders, of which the etiology is closely related to rare coding variants. Filamin B (FLNB) is an actin-binding protein implicated in bone formation. FLNB mutations have been identified in several types of syndromic OFCs and previous studies suggest a role of FLNB in the onset of non-syndromic OFCs (NSOFCs). Here, we report two rare heterozygous variants (p.P441T and p.G565R) in FLNB in two unrelated hereditary families with NSOFCs. Bioinformatics analysis suggests that both variants may disrupt the function of FLNB. In mammalian cells, p.P441T and p.G565R variants are less potent to induce cell stretches than wild type FLNB, suggesting that they are loss-of-function mutations. Immunohistochemistry analysis demonstrates that FLNB is abundantly expressed during palatal development. Importantly, Flnb^(−/−) embryos display cleft palates and previously defined skeletal defects. Taken together, our findings reveal that FLNB is required for development of palates in mice and FLNB is a bona fide causal gene for NSOFCs in humans.

Filamin B:The next hotspot in skeletal research?

Filamin B （FLNB） is a large dimeric actin-binding protein which crosslinks actin cytoskeleton filaments into a dynamic structure. Lip to present, pathogenic mutations in FLNB are solely found to cause skeletal deformities, indicating the important role of FLNB in skeletal development. FLNB-related disorders are classified as spondylocarpotarsal synostosis （SCT）, Larsen syndrome （LS）, atelosteogenesis （AO）, boomerang dysplasia （BD）, and isolated congenital talipes equinovarus, presenting with scoliosis, short- limbed dwarfism, clubfoot, joint dislocation and other unique skeletal abnormalities. Several mecha- nisms of FLNB mutations causing skeletal malformations have been proposed, including delay of ossi- fication in long bone growth plate, reduction of bone mineral density （BMD）, dysregulation of muscle differentiation, ossification of intervertebral disc （IVD）, disturbance of proliferation, differentiation and apoptosis in chondrocytes, impairment of angiogenesis, and hypomotility of osteoblast, chondrocyte and fibroblast. Interventions on FLNB-related diseases require prenatal surveillance by sonography, gene testing in high-risk carriers, and proper orthosis or orthopedic surgeries to correct malformations including scoliosis, cervical spine instability, large joint dislocation, and clubfoot. Gene and cell therapies for FLNB-related diseases are also promising but require further studies.

Mechanisms and Effects on HBV Replication of the Interaction between HBV Core Protein and Cellular Filamin B

Hepatitis B virus(HBV) infection is one of the major problems that threatens global health. There have been many studies on HBV, but the relationship between HBV and host factors is largely unexplored and more studies are needed to clarify these interactions. Filamin B is an actin-binding protein that acts as a cytoskeleton protein, and it is involved in cell development and several signaling pathways. In this study, we showed that filamin B interacted with HBV core protein,and the interaction promoted HBV replication. The interaction between filamin B and core protein was observed in HEK293T, Huh7 and HepG2 cell lines by co-immunoprecipitation and co-localization immnofluoresence. Overexpression of filamin B increased the levels of HBV total RNAs and pre-genome RNA(pg RNA), and improved the secretion level of hepatitis B surface antigen(HBsAg) and hepatitis B e antigen(HBeAg). In contrast, filamin B knockdown inhibited HBV replication, decreased the level of HBV total RNAs and pgRNA, and reduced the secretion level of HBsAg and HBeAg. In addition, we found that filamin B and core protein may interact with each other via four blocks of argentine residues at the C-terminus of core protein. In conclusion, we identify filamin B as a novel host factor that can interact with core protein to promote HBV replication in hepatocytes. Our study provides new insights into the relationship between HBV and host factors and may provide new strategies for the treatment of HBV infection.