Caveolin-1 silencing arrests the proliferation of metastatic lung cancer cells through the inhibition of STAT3 signaling.
ABSTRACT Cav-1 is an essential structural constituent of caveolae implicated in mitogenic signaling, oncogenesis, angiogenesis, neurodegenerative diseases and senescence. Its role as a tumor suppressor gene or as a tumor promoter seems to strictly depend on cell type and tumor stage/grade. The high expression of Cav-1 in some tumors in vivo, amongst which lung adenocarcinoma, is associated with increased tumor aggressiveness, metastatic potential and suppression of apoptosis. In the present study we investigated the role of Cav-1 in metastatic lung cancer proliferation. Cell lines were from metastatic lesions of lung adenocarcinoma (RAL) and of small cell lung carcinoma (SCLC-R1), in which we found Cav-1 expressed at high levels. Results show that siRNA-mediated down-regulation of Cav-1 caused stable arrest of proliferation in both cell lines. A marked reduction of cyclin D1 and of CDK4 expression was evident in the cells transfected with Cav-1 siRNA and consequently of phospho-Rb on ser(795) and ser(780). Furthermore, a significant decrease of the expression of phosphorylated AKT and of its down-stream effectors phosphorylated ERK and STAT3 was evident. Together, these findings indicate that Cav-1 silencing induces an arrest of human metastatic lung proliferation in vitro by a new inhibitory pathway in lung cancer and provide new insights into the molecular mechanisms underlying the pro-survival and tumor-promoting functions of Cav-1.
- SourceAvailable from: Francesco Angrilli[show abstract] [hide abstract]
ABSTRACT: Recent studies have described chromosome 2p gain as a recurrent lesion in chronic lymphocytic leukemia (CLL). We investigated the 2p gain and its relationship with common prognostic biomarkers in a prospective series of 69 clinical monoclonal B-cell lymphocytosis (cMBL) and 218 early stage (Binet A) CLL patients. The 2p gain was detected by FISH in 17 patients (6%, 16 CLL, and 1 cMBL) and further characterized by single nucleotide polymorphism-array. Overall, unfavorable cytogenetic deletions, i.e., del(11)(q23) and del(17)(p13) (P = 0.002), were significantly more frequent in 2p gain cases, as well as unmutated status of IGHV (P < 1 × 10(-4) ) and CD38 (P < 1 × 10(-4) ) and ZAP-70 positive expression (P = 0.003). Furthermore, 2p gain patients had significantly higher utilization of stereotyped B-cell receptors compared with 2p negative patients (P = 0.009), and the incidence of stereotyped subset #1 in 2p gain patients was significantly higher than that found in the remaining CLLs (P = 0.031). Transcriptional profiling analysis identified several genes significantly upregulated in 2p gain CLLs, most of which mapped to 2p. Among these, NCOA1 and ROCK2 are known for their involvement in tumor progression in several human cancers, whereas among those located in different chromosomes, CAV1 at 7q31.1 has been recently identified to play a critical role in CLL progression. Thus, 2p gain can be present since the early stages of the disease, particularly in those cases characterized by other poor prognosis markers. The finding of genes upregulated in the cells with 2p gain provides new insights to define the pathogenic role of this lesion. Am. J. Hematol. 2012. © 2012 Wiley Periodicals, Inc.American Journal of Hematology 09/2012; · 4.00 Impact Factor