Tien Hsu

China Medical University (ROC) · Medicine

Loss of the von Hippel-Lindau (VHL) tumor suppressor gene function accounts for 70-80% of all clear-cell renal cell carcinoma (ccRCC) cases, the most prevalent form of RCC. Accumulating evidence has indicated that ccRCC arises at the site of chronic inflammation; however, how the ccRCC tumor cells interact with the immune components of the microenv...

Loss of the von Hippel–Lindau (VHL) tumor suppressor gene function accounts for 70% to 80% of all clear-cell renal cell carcinoma (ccRCC) cases, the most prevalent form of RCC. Accumulating evidence has indicated that ccRCC arises from sites of chronic inflammation, yet how ccRCC tumor cells interact with immune components of the microenvironment h...

Clear-cell renal cell carcinoma (ccRCC) is the most prevalent subtype of renal cell carcinoma (RCC), and its progression has been linked to chronic inflammation. About 70% of the ccRCC cases are associated with inactivation of the von Hippel–Lindau (VHL) tumor-suppressor gene. However, it is still not clear how mutations in VHL, encoding the substr...

Previous studies have shown that mutations in the tumor suppressor gene von Hippel-Lindau (VHL) can result in the overproduction of reactive oxygen species (ROS) and chronic inflammation and are a significant predisposing factor for the development of clear-cell renal cell carcinoma (ccRCC). To study VHL’s role in ccRCC formation, we previously dev...

MicroRNA-125b, the first microRNA to be identified, is known to promote cardiomyocyte maturation from embryonic stem cells; however, its physiological role remains unclear. To investigate the role of miR-125b in cardiovascular biology, cardiac-specific miR-125b-1 knockout mice were generated. We found that cardiac-specific miR-125b-1 knockout mice...

p>Clear-cell renal cell carcinoma (ccRCC) is the most prevalent histologic subtype of RCC. Interestingly, about 80% of the ccRCC cases are associated with early inactivation of the von Hippel Lindau (VHL) tumor suppressor gene. In our conditional Vhlh knockout mouse model (Hoxb7-Cre-GFP; VhlhloxP/loxP), kidney tissue exhibited a high penetrance of...

Chronic inflammation is the underlying pathological condition that results in fibrotic diseases. More recently, many forms of cancer have also been linked to chronic tissue inflammation. While stromal immune cells and myofibroblasts have been recognized as major contributors of cytokines and growth factors that foster the formation of fibrotic tiss...

The Awd (abnormal wing discs) gene is the Drosophila homolog of human NME1 and NME2 metastasis suppressor genes. These genes play a key role in tumor progression. Extensive studies revealed that intracellular NME1/2 protein levels could be related to either favorable or poor prognosis depending on tissue context. More recently, extracellular activi...

Metastasis remains a clinically unsolved issue in nasopharyngeal carcinoma. Here, we report that higher levels of cytoplasmic leukemia inhibitory factor (LIF) and LIF receptor are correlated with poorer metastasis/recurrence-free survival. Further, single nucleotide variations and signal peptide mutation of LIF are identified in NPC. Cytoplasmic LI...

We report the experimental observation of speeded up collective motion of the monolayer endothelia/cancer mixture on a collagen coated substrate, after the invasion of a small fraction of motile cancer cells into the confluent endothelial monolayer, through disrupting cell-cell junctions. It is found that, with increasing waiting time, the cancer-f...

The Nm23/NME gene family has been under intensive study since Nm23H1/NME1 was identified as the first metastasis suppressor. Inverse correlation between the expression levels of NME1/2 and prognosis has indeed been demonstrated in different tumor cohorts. Interestingly, the presence of NME proteins in the extracellular environment in normal and tum...

Mutations and epigenetic inactivation of the tumor suppressor gene von Hippel-Lindau (VHL) are major causes of clear-cell renal cell carcinoma (ccRCC) that may originate from chronic inflammation. However, the role of VHL loss-of-function in the development of ccRCC via inflammation remains poorly understood. VHL mutant cells exhibit metabolic abno...

Dynamin GTPase (Dyn) plays a critical role in membrane-remodelling events underlying endocytosis. Studies in Drosophila identified a functional interaction between the Dyn homologue, encoded by the shibire (shi) gene, and Abnormal wing discs (Awd), a nucleoside diphosphate kinase (NDPK) that is the homologue of group I Nme human genes. These Drosop...

Background Mutations in the tumor suppressor gene von Hippel-Lindau (VHL) underlie a hereditary cancer syndrome—VHL disease—and are also frequently observed in sporadic renal cell carcinoma of the clear cell type (ccRCC). VHL disease is characterized by malignant and benign tumors in a few specific tissues, including ccRCC, hemangioblastoma and phe...

Dynamin GTPase (Dyn) plays a critical role in membrane-remodelling events underlying endocytosis. Studies in Drosophila identified a functional interaction between the Dyn homolog, encoded by the shibire (shi) gene, and Abnormal wing discs (Awd). These Drosophila studies showed that awd mutations enhance mutant shi phenotype and thus indicated the...

The abnormal wing discs (awd) gene is the Drosophila homologue of the human group I Nme genes coding for metastasis suppressor proteins with NDPK activity. Beyond its NDPK function, many other cellular activities have been assigned to Awd, including a role as endocytic mediator. Earlier genetic studies in Drosophila suggested that Awd could act as...

The gut microbiota is a complex ecosystem that affects the development, nutritional status and immunological responses of the host. Prokaryotes and fungi in the community have the abilities to withstand the adverse conditions of high temperature, low oxygen etc. and to decompose complex organic molecules. The novel approaches of metagenomics and me...

Mutations of the tumor suppressor gene von Hippel-Lindau (VHL) can lead to benign and malignant tumors, including clear-cell renal cell carcinoma (ccRCC). To understand the progression of ccRCC, we generated a novel mouse Vhlh conditional knockout, using Hoxb7-driven Cre that is specific for the collecting ducts and a subset of distal tubules. Thes...

Among the anti-tumor genes (tumor suppressors and metastasis suppressors), the von-Hippel Lindau gene and the Nm23 family of genes are among the more intriguing ones. Both are small (long and short forms of VHL are 30 and 19 kD, respectively, and Nm23 is ~17 kD), and both possess diverse molecular and cellular functions. Despite extensive studies,...

The Drosophila abnormal wing discs (awd) belongs to a highly conserved family of genes implicated in metastasis suppression, metabolic homeostasis and epithelial morphogenesis. The cellular function of the mammalian members of this family, the Nm23 proteins, has not yet been clearly defined. Previous awd genetic analyses unraveled its endocytic rol...

The Drosophila awd gene encodes for the homolog of human metastasis suppressor gene Nm23. Many different functions have been assigned to Awd, including a role as an endocytic mediator. Endocytosis is a critical event for the correct regulation of different signaling pathways, including Notch signaling. We focused our efforts to investigate awd role...

The Drosophila awd gene encodes for the homolog of human metastasis suppressor gene Nm23. Many different functions have been assigned to Awd, including a role as an endocytic mediator. Endocytosis is a critical event for the correct regulation of different signaling pathways, including Notch signaling. We focused our efforts to investigate awd role...

The Drosophila awd gene encodes for the homolog of human metastasis suppressor gene Nm23. Many different functions have been assigned to Awd, including a role as an endocytic mediator. Endocytosis is a critical event for the correct regulation of different signaling pathways, including Notch signaling. We focused our efforts to investigate awd role...

Mutations of the tumor suppressor gene von Hippel-Lindau (VHL) can lead to benign and malignant tumors, including the devastating cancer clear-cell renal cell carcinoma (ccRCC). Using a Cre mouse strain that is driven by the Hoxb7 gene promoter, we have generated a novel Vhl conditional knockout strain that exhibits prominent precancerous lesions i...

The Drosophila awd gene encodes for the homolog of human metastasis suppressor gene Nm23. Many different functions have been assigned to Awd, including a role as an endocytic mediator. Endocytosis is a critical event for the correct regulation of different signaling pathways, including Notch signaling. We focused our efforts to investigate awd role...

2425 Germline heterozygous mutation in the VHL tumor suppressor gene is the underlying genetic defect in VHL disease. Cancer arises when the function of the remaining wildtype allele is lost. VHL patients are prone to develop renal cell carcinoma of the clear cell type (ccRCC) and hemangioblastoma (HB). VHL mutations underlie also the majority of s...

The von Hippel-Lindau tumor suppressor gene (VHL) is best known as an E3 ubiquitin ligase that negatively regulates the hypoxia inducible factor (HIF). VHL mutations are the genetic defects underlying several human diseases including polycythemia, familial VHL tumor syndrome and sporadic renal cell carcinoma. VHL mutations can lead to cell-autonomo...

The PI3 kinase/Akt pathway is commonly deregulated in human cancers, functioning in such processes as proliferation, glucose metabolism, survival and motility. We have previously described a novel function for one of the Akt isoforms (Akt3) in primary endothelial cells: the control of VEGF-induced mitochondrial biogenesis. We sought to determine if...

The von Hippel-Lindau tumor suppressor gene (VHL) has attracted intensive interest not only because its mutations predispose carriers to devastating tumors, but also because it is involved in oxygen sensing under physiological conditions. VHL loss-of-function mutations result in organ-specific tumors, such as hemangioblastoma of the central nervous...

The NME family of genes encodes highly conserved multifunctional proteins that have been shown to participate in nucleic acid metabolism, energy homeostasis, cell signaling, and cancer progression. Some family members, particularly isoforms 1 and 2, have attracted extensive interests because of their potential anti-metastasis activity. Unfortunatel...

Mutations in the human von Hippel-Lindau (VHL) gene are the cause of VHL disease that displays multiple benign and malignant tumors. The VHL gene has been shown to regulate angiogenic potential and glycolic metabolism via its E3 ubiquitin ligase function against the alpha subunit of hypoxia-inducible factor (HIF-α). However, many HIF-independent fu...

Mutations in the human von Hippel-Lindau (VHL) genes are the cause of VHL disease, which displays multiple benign and malignant tumors. The VHL gene has been shown to regulate angiogenic potential and glycolic metabolism via its E3 ubiquitin ligase function against the alpha subunit of hypoxia-inducible factor (HIF). However, many other HIF-indepen...

The expression levels of the metastasis suppressor gene Nm23 have been shown to correlate positively or inversely with prognosis in different cancer cohorts. This indicates that Nm23 may be needed at different expression levels and may function differently in various tissues. Here we report a novel epithelial function of the Drosophila melanogaster...

The metastasis suppressor gene Nm23 is highly conserved from yeast to human, implicating a critical developmental function. Studies in cultured mammalian cells have identified several potential functions, but many have not been directly verified in vivo. Here, we summarize the studies on the Drosophila homolog of the Nm23 gene, named a bnormal w in...

Transforming growth factor-beta (TGF-beta) is an important regulator of physiological connective tissue biosynthesis and plays a central role in pathological tissue fibrosis. Previous studies have established that a biologically active lipid mediator, sphingosine 1-phosphate (S1P), mimics some of the profibrotic functions of TGF-beta through cross-...

von Hippel-Lindau (VHL) disease results from germline and somatic mutations in the VHL tumor suppressor gene and is characterized by highly vascularized tumors. VHL mutations lead to stabilization of hypoxia-inducible factor (HIF), which up-regulates proangiogenic factors such as vascular endothelial growth factor (VEGF). This pathway is therefore...

To understand the role of hypoxia-inducible factor (HIF)-2alpha in regulating sensitivity of renal cancer cells to tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-induced apoptosis, we transfected wild-type and mutant von Hippel Lindau (VHL) proteins into TRAIL-sensitive, VHL-negative A498 cells. We find that wild-type VHL, but not...

The von Hippel-Lindau (VHL) protein serves as a negative regulator of hypoxia-inducible factor (HIF)-alpha subunits. Since HIF regulates critical angiogenic factors such as vascular endothelial growth factor (VEGF) and lesions in VHL gene are present in a majority of the highly vascularized renal cell carcinoma (RCC), it is believed that deregulati...

Border cell migration during Drosophila melanogaster oogenesis is a highly pliable model for studying epithelial to mesenchymal transition and directional cell migration. The process involves delamination of a group of 6 to 10 follicle cells from the epithelium followed by guided migration and invasion through the nurse cell complex toward the oocy...

While studying the developmental functions of the Drosophila dopamine synthesis pathway genes, we noted interesting and unexpected mutant phenotypes in the developing trachea, a tubule network that has been studied as a model for branching morphogenesis. Specifically, Punch (Pu) and pale (ple) mutants with reduced dopamine synthesis show ectopic/ab...

The tumor suppressor VHL (von Hippel-Lindau protein) serves as a negative regulator of hypoxia-inducible factor-alpha subunits. However, accumulated evidence indicates that VHL may play additional roles in other cellular functions. We report here a novel hypoxia-inducible factor-independent function of VHL in cell motility control via regulation of...

The mechanism by which hypoxia induces gene transcription involves the inhibition of HIF-1alpha (hypoxia-inducible factor-1 alpha subunit) PHD (prolyl hydroxylase) activity, which prevents the VHL (von Hippel-Lindau)-dependent targeting of HIF-1alpha to the ubiquitin/proteasome pathway. HIF-1alpha thus accumulates and promotes gene transcription. I...

We show that localized expression of the integrin alpha3 protein is regulated at the level of RNA localization by the human homologue of Drosophila Muscleblind, MLP1/MBLL/MBNL2, a unique Cys3His zinc-finger protein. This is supported by the following observations: MLP1 knockdown abolishes localization of integrin alpha3 to the adhesion complexes; M...

ETS1, the founding member of Ets transcriptional factor family, plays an important role in cell proliferation, differentiation, lymphoid cell development, transformation, angiogenesis, and apoptosis. Previous work has shown that ETS1 represses tumorigenicity of colon carcinoma cells in vivo, and that the p42-ETS1 protein bypasses a defect in apopto...

The Drosophila Akt (dAkt) serine/threonine kinase is a component of the insulin receptor/PI3K signaling pathway that regulates cell growth. Here, we show that this kinase is expressed during Drosophila oogenesis and is required for egg chamber development. Loss of dAkt function in follicle cells causes a cell-autonomous reduction of cell size while...

Primordial germ cells (PGCs) are the first cells specified in many organisms. In Drosophila, as in mammals, PGCs are formed at the posterior end outside of the embryonic proper. They are brought into the gut during gastrulation and then actively migrate through the gut epithelium into the mesoderm. They attach to the future gonadal mesoderm and coa...

The Ets family consists of a large number of evolutionarily conserved transcription factors, many of which have been implicated in tumor progression. Extensive studies on this family of proteins have focused so far mainly on the biochemical properties and cellular functions of individual factors. Since most of the Ets factors can bind to the core c...

We investigated the inter-relationship between two downstream effectors of vascular endothelial growth factor (VEGF), the serine threonine kinase Akt (also known as protein kinase B) and the transcription factor ETS1, during tubulogenesis. Human endothelial cell culture and the in vivo Drosophila tracheal systems are employed in comparative analysi...

Human nm23 has been implicated in suppression of metastasis in various cancers, but the underlying mechanism of such activity has not been fully understood. Using Drosophila tracheal system as a genetic model, we examined the function of the Drosophila homolog of nm23, the awd gene, in cell migration. We show that loss of Drosophila awd results in...

Receptor tyrosine kinase (RTK) signaling is involved in multiple cell fate determination during Drosophila oogenesis. To address the problem of signaling specificity, we sought to systematically document the expression pattern of activated MAP kinase, the downstream effector of RTK signaling. We show that MAP kinase is activated in some of the cell...

The Drosophila C(2)-H(2)-type zinc-finger transcription factor CF2 has been shown to regulate follicular cell fate determination during oogenesis. Here we show that CF2 is also expressed in the developing muscles of the embryo where it first appears at stage 12 at the time of skeletal myoblast fusion. Later it is expressed in all muscle lineages in...

The mammalian cis-trans prolyl isomerase Pin1 and its yeast orthologue Ess1/Ptf1 have been implicated in cell cycle control but a correlation between biochemical and physiological functions has not been established conclusively. Pin1 targets the proline residue carboxy-terminal to the phosphorylated threonine or serine residue, which constitutes pa...

Detailed molecular and genetic studies, coupled with the recent sequencing of the fly genome, have identified eight Ets-related genes in the model organism Drosophila. All show homology to genes in vertebrate species. Functional analyses of some of the Drosophila ets genes have revealed their essential roles in developmental processes such as metam...

von Hippel-Lindau disease is a hereditary cancer syndrome. Mutations in the VHL tumor suppressor gene predispose individuals to highly vascularized tumors. However, VHL-deficient mice die in utero due to a lack of vascularization in the placenta. To resolve the contradiction, we cloned the Drosophila VHL homologue (d-VHL) and studied its function....

The myogenic factor D-MEF2 is required for the proper differentiation of muscle cells during Drosophila embryogenesis and the correct patterning of indirect flight muscles assembled during later metamorphosis. In addition to these essential myogenic functions, mutant D-mef2 adult females are weakly fertile and produce defective eggs. D-MEF2 is expr...