The TGFβ cytokine plays dichotomous roles during tumor progression. In normal and premalignant cancer cells, the TGFβ signaling pathway inhibits proliferation and promotes cell-cycle arrest and apoptosis. However, the activation of this pathway in late-stage cancer cells could facilitate the epithelial-to-mesenchymal transition, stemness, and mobile features to enhance tumorigenesis and metastasis. The opposite functions of TGFβ signaling during tumor progression make it a challenging target to develop anticancer interventions. Nevertheless, the recent discovery of cellular contextual determinants, especially the binding partners of the transcription modulators Smads, is critical to switch TGFβ responses from proapoptosis to prometastasis. In this review, we summarize the recently identified contextual determinants (such as PSPC1, KLF5, 14-3-3ζ, C/EBPβ, and others) and the mechanisms of how tumor cells manage the context-dependent autonomous TGFβ responses to potentiate tumor progression. With the altered expression of some contextual determinants and their effectors during tumor progression, the aberrant molecular prometastatic switch might serve as a new class of theranostic targets for developing anticancer strategies.

The OncoDB.HCC (Author Webpage) is based on physical maps of rodent and human genomes containing quantitative trait loci of rodent HCC models and various human HCC somatic aberrations including chromosomal data from loss of heterozygosity and comparative genome hybridization analyses, altered expression of genes from microarray and proteomic studies, and finally experimental data of published HCC genes. Comprehensive integration of HCC genomic aberration data avoids potential pitfalls of data inconsistency from single genomic approach and provides lines of evidence to reveal somatic aberrations from levels of DNA, RNA to protein. Twenty-nine of 30 (96.7%) novel HCC genes with significant altered expressions in compared between tumor and adjacent normal tissues were validated by RT–PCR in 45 pairs of HCC tissues and by matching expression profiles in 57 HCC patients of re-analyzed Stanford HCC microarray data. Comparative mapping of HCC loci in between human aberrant chromosomal regions and QTLs of rodent HCC models revealed 12 syntenic HCC regions with 2 loci effectively narrowed down to 2 Mb. Together, OncoDB.HCC graphically presents comprehensive HCC data integration, reveals important HCC genes and loci for positional cloning and functional studies, and discloses potential molecular targets for improving HCC diagnosis and therapy.

We extensively allelotyped a panel of 71 microdissected primary surgically resected non small cell lung cancer (NSCLC) tumors to identify chromosomal regions that are likely to contain tumor suppressor genes (TSGs) or associated with clinicopathologic and prognostic effects. Loss of heterozygosity (LOH) was detected by genotyping of 177 microsatellite markers and correlation of LOH with clinicopathologic parameters and prognosis was analyzed. Twenty markers showed an LOH frequency greater than 48%, and 8 of them (2p23.3, 2p24.3, 2q35, 6p22.2, 7p14.3, 7p22.2, 17q24.3 and 21q22.3) were novel in NSCLC. The high LOH regions were confirmed by further aligning continuous LOH regions from another set of 24 NSCLC tissues and defining 7 minimal deletion regions ranging from 1.29 to 12.26 cM. The aberrations of 8 markers showed a significant correlation with alteration of p16 and Rb proteins, suggesting the gene(s) located in the chromosomal loss that may interact with p16/Rb pathway. In addition, markers specifically associated with smoking, histology types and tumor stages were identified and the linked candidate TSGs were suggested. For example, marker D1S1612 closely linked with Mig‐6 gene was associated with smoking patients, squamous cell carcinoma patients and late‐stage patients. Furthermore, 3 markers, D2S2968, D6S2439 and D7S1818, were significantly associated with poor prognosis of NSCLC patients using both univariate and multivariate Cox's regression analyses (p = 0.035, 0.022 and 0.006, respectively). These markers can potentially be used for early lung cancer detection, outcome measurement and the positional cloning of new TSGs whose loss of function contributes to NSCLC tumorigenesis.

Recurrent cancer genome aberrations are indicators of residing crucial cancer genes. Although recent advances in genomic technologies have led to a global view of cancer genome aberrations, the identification of target genes and biomarkers from the aberrant loci remains difficult. To facilitate searches of cancer genes in human hepatocellular carcinoma (HCC), we established a comprehensive protocol to analyze copy number alterations (CNAs) in cancer genomes using high-density single nucleotide polymorphism arrays with unpaired reference genomes. We identified common HCC genes by overlapping the shared aberrant loci in multiple cell lines with functional validation and clinical implications. A total of 653 amplicons and 57 homozygous deletions (HDs) were revealed in 23 cell lines. To search for novel HCC genes, we overlapped aberrant loci to uncover 6 HDs and 126 amplicons shared by at least two cell lines. We selected two novel genes, fibronectin type III domain containing 3B ( FNDC3B ) at the 3q26.3 overlapped amplicon and solute carrier family 29 member 2 ( SLC29A2 ) at the 11q13.2 overlapped amplicon, to investigate their aberrations in HCC tumorigenesis. Aberrant up-regulation of FNDC3B and SLC29A2 occurred in multiple HCC data sets. Knockdown of these genes in amplified cells decreased cell proliferation, anchorage-independent growth, and tumor formation in xenograft models. Importantly, up-regulation of SLC29A2 in HCC tissues was significantly associated with advanced stages ( P = 0.0031), vascular invasion ( P = 0.0353), and poor patient survival ( P = 0.0325). Overexpression of FNDC3B or SLC29A2 in unamplified HCC cells promoted cell proliferation through activation of the signal transducer and activator of transcription 3 signaling pathway. Conclusion: A standardized genome-wide CNA analysis protocol using data from user-generated or public domains normalized with unpaired reference genomes has been established to facilitate high-throughput detection of cancer genes as significant target genes and biomarkers for cancer diagnosis and therapy. (Hepatology 2010)

Pyrimidine metabolic rate limiting enzymes in poorly-differentiated hepatocellular carcinoma are signature genes of cancer stemness and associated with poor prognosis Pyrimidine metabolic rate limiting enzymes in poorly-differentiated hepatocellular carcinoma are signature genes of cancer stemness and associated with poor prognosis