Roy-Akira Saito

Thyroid Transcription Factor-1 Inhibits Transforming Growth Factor-β–Mediated Epithelial-to-Mesenchymal Transition in Lung Adenocarcinoma Cells

Thyroid transcription factor-1 (TTF-1) is expressed in lung cancer, but its functional roles remain unexplored. TTF-1 gene amplification has been discovered in a part of lung adenocarcinomas, and its action as a lineage-specific oncogene is highlighted. Epithelial-to-mesenchymal transition (EMT) is a crucial event for cancer cells to acquire invasive and metastatic phenotypes and can be elicited by transforming growth factor-beta (TGF-beta). Mesenchymal-to-epithelial transition (MET) is the inverse process of EMT; however, signals that induce MET are largely unknown. Here, we report a novel functional aspect of TTF-1 that inhibits TGF-beta-mediated EMT and restores epithelial phenotype in lung adenocarcinoma cells. This effect was accompanied by down-regulation of TGF-beta target genes, including presumed regulators of EMT, such as Snail and Slug. Moreover, silencing of TTF-1 enhanced TGF-beta-mediated EMT. Thus, TTF-1 can exert a tumor-suppressive effect with abrogation of cellular response to TGF-beta and attenuated invasive capacity. We further revealed that TTF-1 down-regulates TGF-beta2 production in A549 cells and that TGF-beta conversely decreases endogenous TTF-1 expression, suggesting that enhancement of autocrine TGF-beta signaling accelerates the decrease of TTF-1 expression and vice versa. These findings delineate potential links between TTF-1 and TGF-beta signaling in lung cancer progression through regulation of EMT and MET and suggest that modulation of TTF-1 expression can be a novel therapeutic strategy for treatment of lung adenocarcinoma.

Forkhead box F1 regulates tumor-promoting properties of cancer-associated fibroblasts in lung cancer.

Cancer-associated fibroblasts (CAF) attract increasing attention as potential cancer drug targets due to their ability to stimulate, for example, tumor growth, invasion, angiogenesis, and metastasis. However, the molecular mechanisms causing the tumor-promoting properties of CAFs remain poorly understood. Forkhead box F1 (FoxF1) is a mesenchymal target of hedgehog signaling, known to regulate mesenchymal-epithelial interactions during lung development. Studies with FoxF1 gain- and loss-of-function fibroblasts revealed that FoxF1 regulates the contractility of fibroblasts, their production of hepatocyte growth factor and fibroblast growth factor-2, and their stimulation of lung cancer cell migration. FoxF1 status of fibroblasts was also shown to control the ability of fibroblasts to stimulate xenografted tumor growth. FoxF1 was expressed in CAFs of human lung cancer and associated with activation of hedgehog signaling. These observations suggest that hedgehog-dependent FoxF1 is a clinically relevant lung CAF-inducing factor, and support experimentally the general concept that CAF properties can be induced by activation of developmentally important transcription factors.

A Smad3 and TTF-1/NKX2-1 complex regulates Smad4-independent gene expression

Thyroid transcription factor-1 (TTF-1, also known as NKX2-1) is a tissue-specific transcription factor in lung epithelial cells. Although TTF-1 inhibits the epithelial-to-mesenchymal transition induced by transforming growth factor-β (TGF-β) in lung adenocarcinoma cells, the mechanism through which TTF-1 inhibits the functions of TGF-β is unknown. Here we show that TTF-1 disrupts the nuclear Smad3-Smad4 complex without affecting the nuclear localization of phospho-Smad3. Genome-wide analysis by chromatin immunoprecipitation followed by sequencing revealed that TTF-1 colocalizes with Smad3 on chromatin and alters Smad3-binding patterns throughout the genome, while TTF-1 generally inhibits Smad4 binding to chromatin. Moreover, Smad3 binds to chromatin together with TTF-1, but not with Smad4, at some Smad3-binding regions when TGF-β signaling is absent, and knockdown of Smad4 expression does not attenuate Smad3 binding in these regions. Thus, TTF-1 may compete with Smad4 for interaction with Smad3, and in the presence of TTF-1, Smad3 regulates the transcription of certain genes independently of Smad4. These findings provide a new model of regulation of TGF-β-Smad signaling by TTF-1.

A near-infrared catalogue of the Galactic novae in the VVV survey area

Context. Near-infrared data on classical novae contain useful information about the ejected gas mass and the thermal emission by dust formed during eruption, and provide independent methods to classify the objects according to the colour of their progenitors, and the fading rate and features seen after eruption. The VISTA Variables in the V�a L�ctea survey (VVV) is a near-IR ESO Public Survey mapping the Milky Way bulge and southern plane. Data taken during 2010-2011 covered the entire area in the JHK s bands plus some epochs in K s -band of the ongoing VVV variability campaign. Aims: We used the VVV data to create a near-IR catalogue of the known Galactic novae in the 562 sq. deg. area covered by VVV. We also compiled the information about novae from the variability tables of the VVV variability campaign. Methods: We used the novae list provided by VSX/AAVSO catalogue to search for all objects within the VVV area. From the 140 novae, we were able to retrieve the JHK s colours of 93 objects. We also checked in the ongoing VVV variability campaign for the light curves of novae that erupted in the last years. Results: The VVV near-IR catalogue of novae contains JHK s photometry of 93 objects completed as of December 2012. VVV allows to monitor objects within up to ?K s ~ 10 mag range. VVV images can also be used to discover and study novae by searching for the expanding shell. Since objects are seen at different distances and reddening levels, the colour-magnitude and colour-colour diagrams show the novae spread in magnitude as well as in colour. Dereddened colours and reddening-free indices were used with caution and cannot be a good approach in all cases since the distance and spectral features prevent more conclusive results for some extreme objects. Light curves for some recent novae are presented. Conclusions: Thanks to its high spatial resolution in the near IR and wide K s -range, the VVV survey can be a major contributor to the search for and study of novae in the most crowded and high-extinction regions of the Milky Way. The VVV survey area contains ~35% of all known novae in the Galaxy. Based on observations taken within the ESO VISTA Public Survey VVV, Programme ID 179.B-2002.

Milky Way demographics with the VVV survey. IV. PSF photometry from almost one billion stars in the Galactic bulge and adjacent southern disk

Accepted for publication in a forthcoming issue of Astronomy & Astrophysics. Reproduced with permission from Astronomy & Astrophysics.

Stellar variability in the VVV survey : Overview and first results

The Vista Variables in the V´oa Lactea (VVV) ESO Public Survey is an ongoing time-series, near-infrared (IR) survey of the Galactic bulge and an adjacent portion of the inner disk, covering 562 square degrees of the sky, using ESOs VISTA telescope. The survey has provided su- perb multi-color photometry in 5 broadband filters (Z, Y , J, H, and Ks), leading to the best map of the inner Milky Way ever obtained, par- ticularly in the near-IR. The main variability part of the survey, which is focused on Ks-band observations, is currently underway, with bulge fields having been observed between 31 and 70 times, and disk fields be- tween 17 and 36 times. When the survey is complete, bulge (disk) fields