Identification of RASSF8 as a candidate lung tumor suppressor gene

Falvella, Felicia Stefania; Manenti, Giacomo; Spinola, Monica; Pignatiello, Carmen; Conti, Bárbara; Pastorino, Ugo; Dragani, Tommaso A.

doi:10.1038/sj.onc.1209422

Cited by 51 publications

(53 citation statements)

References 20 publications

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“…It has been recently suggested that RASSF8 may be a novel tumor suppressor gene in lung cancer (Falvella et al, 2006). Overexpression of this isoform suppresses anchorage-independent growth of the lung cancer cell lines A549 and H520 (Falvella et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…Overexpression of this isoform suppresses anchorage-independent growth of the lung cancer cell lines A549 and H520 (Falvella et al, 2006). As overexpression can often lead to toxicity, we aimed to investigate the effects of decreased levels of RASSF8 (as observed in lung cancer) on cell growth by RNAimediated RASSF8 depletion.…”

Section: Discussionmentioning

confidence: 99%

“…Recently we have shown that Xenopus RASSF7 is a centrosome-associated protein and is required for completing mitosis (Sherwood et al, 2008). There is some evidence suggesting that RASSF8 may act as a tumor suppressor gene in lung cancer (Falvella et al, 2006). RASSF9 has been shown to bind RAS proteins and is linked to vesicle trafficking (Chen et al, 1998;RodriguezViciana et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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The RASSF8 candidate tumor suppressor inhibits cell growth and regulates the Wnt and NF-κB signaling pathways

et al. 2010

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The Ras-assocation domain family (RASSF) of tumor suppressor proteins until recently contained six proteins named RASSF1-6. Recently, four novel family members, RASSF7-10, have been identified by homology searches for RA-domain-containing proteins. These additional RASSF members are divergent and structurally distinct from RASSF1-6, containing an N-terminal RA domain and lacking the Sav/RASSF/Hpo (SARAH) domain. Here, we show that RASSF8 is ubiquitously expressed throughout the murine embryo and in normal human adult tissues. Functionally, RNAi-mediated knockdown of RASSF8 in non-small-cell lung cancer (NSCLC) cell lines, increased anchorage-independent growth in soft agar and enhanced tumor growth in severe combined immunodeficiency (SCID) mice. Furthermore, EdU staining of RASSF8-depleted cells showed growth suppression in a manner dependent on contact inhibition. We show that endogenous RASSF8 is not only found in the nucleus, but is also membrane associated at sites of cell-cell adhesion, co-localizing with the adherens junction (AJ) component b-catenin and binding to E-cadherin. Following RASSF8 depletion in two different lung cancer cell lines using alternative small interfering RNA (siRNA) sequences, we show that AJs are destabilized and E-cadherin is lost from the cell membrane. The AJ components b-catenin and p65 are also lost from sites of cell-cell contact and are relocalized to the nucleus with a concomitant increase in b-catenin-dependent and nuclear factorjB (NF-jB)-dependent signaling following RASSF8 depletion. RASSF8 may also be required to maintain actin -cytoskeletal organization since immunofluorescence analysis shows a striking disorganization of the actincytoskeleton following RASSF8 depletion. Accordingly, scratch wound healing studies show increased cellular migration in RASSF8-deficient cells. These results implicate RASSF8 as a tumor suppressor gene that is essential for maintaining AJs function in epithelial cells and have a role in epithelial cell migration.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The RASSF8 candidate tumor suppressor inhibits cell growth and regulates the Wnt and NF-κB signaling pathways

et al. 2010

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“…As a result, the function of RASSF7 and RASSF8 may differ considerably from RASSF1-6. Nevertheless, one isoform of RASSF8 is downregulated in lung adenocarcinomas and its re-expression reduces anchorageindependent growth of lung tumour cells (Falvella et al, 2006). This has been observed for many RASSF members including RASSF1A.…”

Section: Rassf1mentioning

confidence: 95%

“…RASSF3A is not methylated in human tumours and RASSF6 is not methylated in colorectal cancer (Hesson et al, , 2005Akino et al, 2005). In addition, RASSF7 and RASSF8 have recently been identified (UCSC Genome Browser; Falvella et al, 2006). These additional family members also contain a RA domain of the RalGDS/ AF-6 variety but importantly lack SARAH domains.…”

Section: Rassf1mentioning

confidence: 99%

Evaluation of the 3p21.3 tumour-suppressor gene cluster

2007

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DNA fingerprinting tags novel altered chromosomal regions and identifies the involvement of SOX5 in the progression of prostate cancer

Chan

Woolcock

et al. 2009

Intl Journal of Cancer

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Identification of genomic alterations associated with the progression of prostate cancer may facilitate the better understanding of the development of this highly variable disease. Matched normal, premalignant high-grade prostatic intraepithelial neoplasia and invasive prostate carcinoma cells were procured by laser capture microdissection (LCM) from human radical prostatectomy specimens. From these cells, comparative DNA fingerprints were generated by a modified PCR-based technique called scanning of microdissected archival lesion (SMAL)-PCR. Recurrent polymorphic fingerprint fragments were used in tagging altered chromosomal regions. Altered regions were found at cytobands 1p31. 3, 1q44, 2p23.1, 3p26.3, 3q22.3, 4q22.3, 4q35.2, 5q23.2, 8q22.3, 8q24.13, 9q21.3, 9q22.32, 10q11.21, 11p13, 12p12.1, 13q12.1, 16q12.2 and 18q21.31. Candidate genes in the surrounding area that may possibly harbor mutations that change normal prostatic cells to progress into their tumor stages were proposed. Of these fragments, a 420 bp alteration, absent in all 26 normal samples screened, was observed in 2 tumors. This fragment was cloned, sequenced and localized to chromosome 12p12.1. Within this region, candidate gene sex determining region Y-box 5 (SOX5) was proposed. Further studies of SOX5 in cell lines, xenografts and human prostate specimens, at both the RNA and protein levels, found overexpression of the gene in tumors. This overexpression was then subsequently found by fluorescent in situ hybridization to be caused by amplification of the region. In conclusion, our results suggest LCM coupled with SMAL-PCR DNA fingerprinting is a useful method for the screening and identification of chromosomal regions and genes associated with cancer development. Further, overexpression of SOX5 is associated with prostate tumor progression and early development of distant metastasis.

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Identification of RASSF8 as a candidate lung tumor suppressor gene

Cited by 51 publications

References 20 publications

The RASSF8 candidate tumor suppressor inhibits cell growth and regulates the Wnt and NF-κB signaling pathways

The RASSF8 candidate tumor suppressor inhibits cell growth and regulates the Wnt and NF-κB signaling pathways

Evaluation of the 3p21.3 tumour-suppressor gene cluster

DNA fingerprinting tags novel altered chromosomal regions and identifies the involvement of SOX5 in the progression of prostate cancer

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