Chiou-hwa Yuh | National Health Research Institutes (original) (raw)

Papers by Chiou-hwa Yuh

Research paper thumbnail of Creatine and L-carnitine attenuate muscular laminopathy in the LMNA mutation transgenic zebrafish

LMNA gene mutations cause debilitating striated muscle laminopathies, affecting cardiac and skele... more LMNA gene mutations cause debilitating striated muscle laminopathies, affecting cardiac and skeletal muscles, with limited treatments. This study investigates five LMNA mutations using zebrafish models. Transgenic zebrafish expressing wild-type LMNAand each mutation are extensively profiled for morphology, behavior, and histology, with a focus on skeletal muscles. Drug screening and transcriptomic analysis uncover altered gene expression. Intriguing phenotypes emerge in adult zebrafish with LMNA mutations. LMNA(W520G) variants exhibit a mortality rate within three months. LMNA(A539V) fish exhibit abnormalities in F0 adults and crooked bodies in F1 adults, similar to LMNA(R453W) F1 fish. Larvae of LMNA(L35P), LMNA(E358K), and LMNA(R453W) transgenic fish swim slower than AB(WT) and LMNA(WT) in DanioVision. All LMNA transgenic adult fish, except LMNA(E358K), show reduced swimming speed and muscle endurance compared to AB(WT) in T-maze and swimming tunnel tests. Histochemical staining r...

Research paper thumbnail of Figure S5 from Lymphotoxin-β Interacts with Methylated EGFR to Mediate Acquired Resistance to Cetuximab in Head and Neck Cancer

Interaction between LTβ and methylated EGFR activates EGFR and induces cetuximab resistance

Research paper thumbnail of Data from HMDB and 5-AzadC Combination Reverses Tumor Suppressor CCAAT/Enhancer-Binding Protein Delta to Strengthen the Death of Liver Cancer Cells

Research paper thumbnail of Stabilization of AMPK/PFKL/RPIA in the Glycolytic Bodies Transduces IL6/STAT3 Signal in Hepatocarcinogenesis

bioRxiv (Cold Spring Harbor Laboratory), Mar 4, 2024

Metabolic reprogramming is a pivotal characteristic of cancer, yet the intricate interplay betwee... more Metabolic reprogramming is a pivotal characteristic of cancer, yet the intricate interplay between glycolysis and the pentose phosphate pathway (PPP) remains elusive. This study unveils the pivotal role of 6-phosphofructokinase liver type (PFKL) in glycolysis and ribose 5-phosphate isomerase A (RPIA) in PPP, orchestrating liver tumorigenesis. PFKL, the rate-limiting enzyme in glycolysis, stabilizes RPIA by impeding ubiquitination/proteasome activity. The pro-inflammatory and tumor cytokine interleukin 6 activates pSTAT3 which binds to the promoter region and activates AMPK and PFKL transcription. Furthermore, pAMPK stabilizes PFKL protein by preventing proteasome degradation in hepatoma cells. Inhibiting PFKL, AMPK, and STAT3 genetically or pharmacologically can reduce glycolysis, ATP production, resulting in reduction of hepatoma cell proliferation and migration. Intriguingly, the PFKL, AMPK, RPIA, and PKM2 are co-localized in the Glycolytic body (G-body) which starts forming at chronic hepatitis, dramatically increases during active hepatitis, and the size of G-bodies becomes bigger from cirrhosis to hepatocellular carcinoma. Furthermore, using Bimolecular fluorescence complementation (BiFC) assay, we demonstrated that PFKL and RPIA direct interacts. Targeting AMPK or STAT3 significantly reduced tumor formation and lipid accumulation in zebrafish models, suggesting the STAT3/AMPK/PFKL axis as a potential therapeutic avenue for liver cancer treatment.

Research paper thumbnail of Supplementary Figure 1-6 from HMDB and 5-AzadC Combination Reverses Tumor Suppressor CCAAT/Enhancer-Binding Protein Delta to Strengthen the Death of Liver Cancer Cells

Research paper thumbnail of Supplementary Table 1-5 from HMDB and 5-AzadC Combination Reverses Tumor Suppressor CCAAT/Enhancer-Binding Protein Delta to Strengthen the Death of Liver Cancer Cells

Supplementary Table 1. Expression of CEBPD and its correlation with clinicopathological parameter... more Supplementary Table 1. Expression of CEBPD and its correlation with clinicopathological parameters. Supplementary Table 2. Univariate log rank analysis for prognostic factors in 90 patients with follow-up. Supplementary Table 3. Multivariate survival analyses for prognostic factors in 90 patients with follow-up. Supplementary Table 4: List of primer sequences Supplementary Table 5: List of antibodies for Western blot

Research paper thumbnail of C/EBP-Like Proteins Binding to the Functional Box-α and Box-β of the Second Enhancer of Hepatitis B Virus

Molecular and Cellular Biology, Oct 1, 1991

The second enhancer (enhancer II) of hepatitis B virus is functionally liver specific. Located wi... more The second enhancer (enhancer II) of hepatitis B virus is functionally liver specific. Located within an open reading frame of the virus and immediately upstream of the initiation sites of viral major transcripts, enhancer II furnishes a unique model for use in investigating the structure and function of an enhancer. In this study, two functional constituents, a 23-bp box-alpha and a 12-bp box-beta, are identified as being both necessary and sufficient for enhancer II function. Examination of the box-alpha and box-beta sequences reveals a weak homology to the extended consensus for a C/EBP binding site. Gel shift and footprinting analyses indicate that multiple proteins bind to these sequences and thus are candidate transcription factors that mediate the enhancer function. One heat-resistant protein, protein a, and one heat-sensitive protein, protein b, bind to box-alpha. Protein a, which binds to box-alpha in a way indistinguishable from that seen with a recombinant C/EBP, appears not to be identical to C/EBP in that the binding of protein a requires a minimal sequence larger than the canonical C/EBP sites. Two box-beta-binding proteins, c and d, show greater affinity for the C/EBP consensus than for box-beta. However, both proteins c and d are relatively heat sensitive and display a distinct sequence preference from the recombinant C/EBP protein. Since the function of enhancer II is strictly dependent on a bipartite architecture, this system provides a unique model for studies of how the interactions of its binding proteins lead to the enhancer function.

Research paper thumbnail of Figure S3 from Lymphotoxin-β Interacts with Methylated EGFR to Mediate Acquired Resistance to Cetuximab in Head and Neck Cancer

Activation of NF-κB in cetuximab-resistant cells

Research paper thumbnail of supplemental information from Lymphotoxin-β Interacts with Methylated EGFR to Mediate Acquired Resistance to Cetuximab in Head and Neck Cancer

Includes legends to 5 supplementary figures, supplementary methods, and supplementary references

Research paper thumbnail of Table S1 from Lymphotoxin-β Interacts with Methylated EGFR to Mediate Acquired Resistance to Cetuximab in Head and Neck Cancer

S1A: S1A: Gene expression profile of OECM1-CtxR cells (1.5 folds, 1955 identities); S1B: Cetuxima... more S1A: S1A: Gene expression profile of OECM1-CtxR cells (1.5 folds, 1955 identities); S1B: Cetuximab resistance signature (170 identities); S1C:Gene expression profiles in FaDu-Snail cells (2.5 folds with FPKM>1, 477 genes)

Research paper thumbnail of Figure S2 from Lymphotoxin-β Interacts with Methylated EGFR to Mediate Acquired Resistance to Cetuximab in Head and Neck Cancer

Snail locates upstream to LTβ upregulates its expression, and LTβ induces EMT

Research paper thumbnail of Figure S1 from Lymphotoxin-β Interacts with Methylated EGFR to Mediate Acquired Resistance to Cetuximab in Head and Neck Cancer

Generation and characterization of the cetuximab-resistant head and neck cancer cells

Research paper thumbnail of Identification of Sequence-Specific DNA Binding Proteins

Methods in Cell Biology, 2004

The plastid gene psbD encodes the photosystem II reaction center chlorophyll protein D2. psbD is ... more The plastid gene psbD encodes the photosystem II reaction center chlorophyll protein D2. psbD is located in a complex operon that includes psbC, psbK, psbl, orf62, and tmG. The operon is transcribed from at least three different promoters. One of the psbD promoters is differentially activated when plants are exposed t o blue light. In this study, the psbD blue light-responsive promoter was accurately transcribed in vitro in high-salt extracts of barley plastids. Transcription required supercoiled templates and was inhibited by tagetitoxin, an inhibitor of plastid transcription. Escherichia coli RNA polymerase did not recognize the psbD light-responsive promoter with the same specificity as plastid RNA polymerase. Deletion analyses demonstrated that sequences between-39 and-68, upstream of the transcription initiation site, were required for transcription of the psbD blue light-responsive promoter. This DNA region is highly conserved among plant species and contains multiple AAG sequences. Gel shift assays and DNase I footprinting experiments demonstrated that the AAG-rich DNA sequence interacts with a sequence-specific DNA binding factor termed AGF. Point mutations in the AAG c i s element decreased binding of AGF and inhibited transcription from the psbD light-responsive promoter. We concluded that AGF is an essential factor required for transcription of the psbD light-responsive promoter.

Research paper thumbnail of A liver-specific nuclear factor interacts with the promoter region of the large surface protein gene of human hepatitis B virus

Molecular and Cellular Biology, Nov 1, 1989

The outer envelope of the 42-nm virion of the human hepatitis B virus (HBV) is composed of the la... more The outer envelope of the 42-nm virion of the human hepatitis B virus (HBV) is composed of the large, the middle, and the major surface proteins. Whereas the middle and the major surface proteins are transcribed from the SPIH promoter of the pre-S/S gene, the large surface protein is transcribed from the SPI promoter located upstream of SPIl. We have previously shown that transcription of SPI (comprising nucleotides [nt]-380 to + 17) occurs preferentially in differentiated hepatoma cell lines (H. K. Chang and L. P. Ting, Virology 170:176-183, 1989). In this report, we further demonstrated that a sequence of 95 base pairs in the upstream region of SPI (nt-95 to +17) was necessary and sufficient for such preferential expression in differentiated hepatoma cells. By analysis of the expression of the chloramphenicol acetyltransferase gene in a series of mutants with deletions at the 5' end of SPI, we identified a positive transcriptional cis-acting element mapping at nt-95 to-72 which appears to play a key role in the regulation of the expression of the large surface protein. This region shared a high degree of sequence homology with regulatory sequences of several liver-specific genes from human, mouse, and rat, with a consensus sequence (G/A)GTTA(A/C)TNNT(C/T) NNC(A/C). We further identified a nuclear factor present in the nuclear extracts of differentiated human hepatoma cell lines which interacted specifically with this element of the SPI promoter. This nuclear factor was similar to the rat liver-specific factor HNF-1, since an oligonucleotide containing the recognition sequence of HNF-1 could efficiently compete for the human factor in a footprinting assay. The sequence at nt-93 to-68 which was bound by this factor in SPI was termed the EINF-1-binding element. Activation of the SPI promoter by human differentiated hepatocyte nuclear factor 1, described in this report, probably explains, first, the formation of the 42-nm virion specifically in liver but not in several other tissues despite the synthesis of the middle and the major surface proteins in those tissues, and second, why only differentiated hepatoma cell lines are able to produce 42-nm-like virion particles on transfection by HBV DNA.

Research paper thumbnail of Supplementary Figure legends from HMDB and 5-AzadC Combination Reverses Tumor Suppressor CCAAT/Enhancer-Binding Protein Delta to Strengthen the Death of Liver Cancer Cells

Supplementary Figure legends

Research paper thumbnail of Supplementary Method from HMDB and 5-AzadC Combination Reverses Tumor Suppressor CCAAT/Enhancer-Binding Protein Delta to Strengthen the Death of Liver Cancer Cells

Research paper thumbnail of Transcriptional regulation of precore and pregenomic RNAs of hepatitis B virus

Journal of Virology, Jul 1, 1992

Research paper thumbnail of Ribose-5-phosphate isomerase A overexpression promotes liver cancer development in transgenic zebrafish via activation of ERK and β-catenin pathways

Carcinogenesis, Nov 12, 2018

Dysregulation of the enzymes involved in the pentose phosphate pathway (PPP) is known to promote ... more Dysregulation of the enzymes involved in the pentose phosphate pathway (PPP) is known to promote tumorigenesis. Our recent study demonstrated that ribose-5-phosphate isomerase (RPIA), a key regulator of the PPP, regulates hepatoma cell proliferation and colony formation. Our studies in zebrafish reveal that RPIA-mediated hepatocarcinogenesis requires extracellular signal-regulated kinase (ERK) and β-catenin signaling. To further investigate RPIA-mediated hepatocarcinogenesis, two independent lines of transgenic zebrafish expressing human RPIA in the liver were generated. These studies reveal that RPIA overexpression triggers lipogenic factor/enzyme expression, steatosis, fibrosis and proliferation of the liver. In addition, the severity of fibrosis and the extent of proliferation are positively correlated with RPIA expression levels. Furthermore, RPIA-mediated induction of hepatocellular carcinoma (HCC) requires the ERK and β-catenin signaling pathway but is not dependent upon transaldolase levels. Our study presents a mechanism for RPIAmediated hepatocarcinogenesis and suggests that RPIA represents a valuable therapeutic target for the treatment of HCC.

Research paper thumbnail of Cytoplasmic LIF reprograms invasive mode to enhance NPC dissemination through modulating YAP1-FAK/PXN signaling

Nature Communications, Nov 30, 2018

Metastasis remains a clinically unsolved issue in nasopharyngeal carcinoma. Here, we report that ... more 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 LIF reprograms the invasive mode from collective to mesenchymal migration via acquisition of EMT and invadopodia-associated characteristics. Higher cytoplasmic LIF enhances cancer vascular dissemination and local invasion mechanistically through modulation of YAP1-FAK/PXN signaling. Immunohistochemical analyses of NPC biopsies reveal a positive correlation of cytoplasmic LIF expression with focal adhesion kinases. Pharmaceutical intervention with AZD0530 markedly reverses LIF-mediated cancer dissemination and local invasion through promotion of cytoplasmic accumulation of YAP1 and suppression of focal adhesion kinases. Given the significant role of LIF/YAP1-focal adhesion signaling in cancer dissemination, targeting of this pathway presents a promising opportunity to block metastasis.

Research paper thumbnail of Supplementary Figure 1-6 from HMDB and 5-AzadC Combination Reverses Tumor Suppressor CCAAT/Enhancer-Binding Protein Delta to Strengthen the Death of Liver Cancer Cells

Supplemental Figure 1. Anti-cancer drugs induce CEBPD expression in liver cancer cells. Supplemen... more Supplemental Figure 1. Anti-cancer drugs induce CEBPD expression in liver cancer cells. Supplemental Figure 2. Scheme of depression of epigenetic effects to enhance HMDB-induced CEBPD expression and apoptosis. Supplemental Figure 3. (Related to Figure 5) The p38/CREB pathway mediates HMDB-induced CEBPD transcriptional activation and CEBPD participates in HMDB-induced apoptosis in liver cancer cells. Supplemental Figure 4. (Related to Figure 5) Combinatorial treatment of HMDB and 5-AzadC can additively affect cell death. Supplemental Figure 5. (Related to Figure 5) Enhanced cytotoxic effects of HMDB combined with 5-AzadC on Huh7 and HepG2 cells. Supplemental Figure 6. (Related to Figure 5) Loss of CEBPD attenuated dual treatment-induced tumor killing in liver cancer cells.

Research paper thumbnail of Creatine and L-carnitine attenuate muscular laminopathy in the LMNA mutation transgenic zebrafish

LMNA gene mutations cause debilitating striated muscle laminopathies, affecting cardiac and skele... more LMNA gene mutations cause debilitating striated muscle laminopathies, affecting cardiac and skeletal muscles, with limited treatments. This study investigates five LMNA mutations using zebrafish models. Transgenic zebrafish expressing wild-type LMNAand each mutation are extensively profiled for morphology, behavior, and histology, with a focus on skeletal muscles. Drug screening and transcriptomic analysis uncover altered gene expression. Intriguing phenotypes emerge in adult zebrafish with LMNA mutations. LMNA(W520G) variants exhibit a mortality rate within three months. LMNA(A539V) fish exhibit abnormalities in F0 adults and crooked bodies in F1 adults, similar to LMNA(R453W) F1 fish. Larvae of LMNA(L35P), LMNA(E358K), and LMNA(R453W) transgenic fish swim slower than AB(WT) and LMNA(WT) in DanioVision. All LMNA transgenic adult fish, except LMNA(E358K), show reduced swimming speed and muscle endurance compared to AB(WT) in T-maze and swimming tunnel tests. Histochemical staining r...

Research paper thumbnail of Figure S5 from Lymphotoxin-β Interacts with Methylated EGFR to Mediate Acquired Resistance to Cetuximab in Head and Neck Cancer

Interaction between LTβ and methylated EGFR activates EGFR and induces cetuximab resistance

Research paper thumbnail of Data from HMDB and 5-AzadC Combination Reverses Tumor Suppressor CCAAT/Enhancer-Binding Protein Delta to Strengthen the Death of Liver Cancer Cells

Research paper thumbnail of Stabilization of AMPK/PFKL/RPIA in the Glycolytic Bodies Transduces IL6/STAT3 Signal in Hepatocarcinogenesis

bioRxiv (Cold Spring Harbor Laboratory), Mar 4, 2024

Metabolic reprogramming is a pivotal characteristic of cancer, yet the intricate interplay betwee... more Metabolic reprogramming is a pivotal characteristic of cancer, yet the intricate interplay between glycolysis and the pentose phosphate pathway (PPP) remains elusive. This study unveils the pivotal role of 6-phosphofructokinase liver type (PFKL) in glycolysis and ribose 5-phosphate isomerase A (RPIA) in PPP, orchestrating liver tumorigenesis. PFKL, the rate-limiting enzyme in glycolysis, stabilizes RPIA by impeding ubiquitination/proteasome activity. The pro-inflammatory and tumor cytokine interleukin 6 activates pSTAT3 which binds to the promoter region and activates AMPK and PFKL transcription. Furthermore, pAMPK stabilizes PFKL protein by preventing proteasome degradation in hepatoma cells. Inhibiting PFKL, AMPK, and STAT3 genetically or pharmacologically can reduce glycolysis, ATP production, resulting in reduction of hepatoma cell proliferation and migration. Intriguingly, the PFKL, AMPK, RPIA, and PKM2 are co-localized in the Glycolytic body (G-body) which starts forming at chronic hepatitis, dramatically increases during active hepatitis, and the size of G-bodies becomes bigger from cirrhosis to hepatocellular carcinoma. Furthermore, using Bimolecular fluorescence complementation (BiFC) assay, we demonstrated that PFKL and RPIA direct interacts. Targeting AMPK or STAT3 significantly reduced tumor formation and lipid accumulation in zebrafish models, suggesting the STAT3/AMPK/PFKL axis as a potential therapeutic avenue for liver cancer treatment.

Research paper thumbnail of Supplementary Figure 1-6 from HMDB and 5-AzadC Combination Reverses Tumor Suppressor CCAAT/Enhancer-Binding Protein Delta to Strengthen the Death of Liver Cancer Cells

Research paper thumbnail of Supplementary Table 1-5 from HMDB and 5-AzadC Combination Reverses Tumor Suppressor CCAAT/Enhancer-Binding Protein Delta to Strengthen the Death of Liver Cancer Cells

Supplementary Table 1. Expression of CEBPD and its correlation with clinicopathological parameter... more Supplementary Table 1. Expression of CEBPD and its correlation with clinicopathological parameters. Supplementary Table 2. Univariate log rank analysis for prognostic factors in 90 patients with follow-up. Supplementary Table 3. Multivariate survival analyses for prognostic factors in 90 patients with follow-up. Supplementary Table 4: List of primer sequences Supplementary Table 5: List of antibodies for Western blot

Research paper thumbnail of C/EBP-Like Proteins Binding to the Functional Box-α and Box-β of the Second Enhancer of Hepatitis B Virus

Molecular and Cellular Biology, Oct 1, 1991

The second enhancer (enhancer II) of hepatitis B virus is functionally liver specific. Located wi... more The second enhancer (enhancer II) of hepatitis B virus is functionally liver specific. Located within an open reading frame of the virus and immediately upstream of the initiation sites of viral major transcripts, enhancer II furnishes a unique model for use in investigating the structure and function of an enhancer. In this study, two functional constituents, a 23-bp box-alpha and a 12-bp box-beta, are identified as being both necessary and sufficient for enhancer II function. Examination of the box-alpha and box-beta sequences reveals a weak homology to the extended consensus for a C/EBP binding site. Gel shift and footprinting analyses indicate that multiple proteins bind to these sequences and thus are candidate transcription factors that mediate the enhancer function. One heat-resistant protein, protein a, and one heat-sensitive protein, protein b, bind to box-alpha. Protein a, which binds to box-alpha in a way indistinguishable from that seen with a recombinant C/EBP, appears not to be identical to C/EBP in that the binding of protein a requires a minimal sequence larger than the canonical C/EBP sites. Two box-beta-binding proteins, c and d, show greater affinity for the C/EBP consensus than for box-beta. However, both proteins c and d are relatively heat sensitive and display a distinct sequence preference from the recombinant C/EBP protein. Since the function of enhancer II is strictly dependent on a bipartite architecture, this system provides a unique model for studies of how the interactions of its binding proteins lead to the enhancer function.

Research paper thumbnail of Figure S3 from Lymphotoxin-β Interacts with Methylated EGFR to Mediate Acquired Resistance to Cetuximab in Head and Neck Cancer

Activation of NF-κB in cetuximab-resistant cells

Research paper thumbnail of supplemental information from Lymphotoxin-β Interacts with Methylated EGFR to Mediate Acquired Resistance to Cetuximab in Head and Neck Cancer

Includes legends to 5 supplementary figures, supplementary methods, and supplementary references

Research paper thumbnail of Table S1 from Lymphotoxin-β Interacts with Methylated EGFR to Mediate Acquired Resistance to Cetuximab in Head and Neck Cancer

S1A: S1A: Gene expression profile of OECM1-CtxR cells (1.5 folds, 1955 identities); S1B: Cetuxima... more S1A: S1A: Gene expression profile of OECM1-CtxR cells (1.5 folds, 1955 identities); S1B: Cetuximab resistance signature (170 identities); S1C:Gene expression profiles in FaDu-Snail cells (2.5 folds with FPKM>1, 477 genes)

Research paper thumbnail of Figure S2 from Lymphotoxin-β Interacts with Methylated EGFR to Mediate Acquired Resistance to Cetuximab in Head and Neck Cancer

Snail locates upstream to LTβ upregulates its expression, and LTβ induces EMT

Research paper thumbnail of Figure S1 from Lymphotoxin-β Interacts with Methylated EGFR to Mediate Acquired Resistance to Cetuximab in Head and Neck Cancer

Generation and characterization of the cetuximab-resistant head and neck cancer cells

Research paper thumbnail of Identification of Sequence-Specific DNA Binding Proteins

Methods in Cell Biology, 2004

The plastid gene psbD encodes the photosystem II reaction center chlorophyll protein D2. psbD is ... more The plastid gene psbD encodes the photosystem II reaction center chlorophyll protein D2. psbD is located in a complex operon that includes psbC, psbK, psbl, orf62, and tmG. The operon is transcribed from at least three different promoters. One of the psbD promoters is differentially activated when plants are exposed t o blue light. In this study, the psbD blue light-responsive promoter was accurately transcribed in vitro in high-salt extracts of barley plastids. Transcription required supercoiled templates and was inhibited by tagetitoxin, an inhibitor of plastid transcription. Escherichia coli RNA polymerase did not recognize the psbD light-responsive promoter with the same specificity as plastid RNA polymerase. Deletion analyses demonstrated that sequences between-39 and-68, upstream of the transcription initiation site, were required for transcription of the psbD blue light-responsive promoter. This DNA region is highly conserved among plant species and contains multiple AAG sequences. Gel shift assays and DNase I footprinting experiments demonstrated that the AAG-rich DNA sequence interacts with a sequence-specific DNA binding factor termed AGF. Point mutations in the AAG c i s element decreased binding of AGF and inhibited transcription from the psbD light-responsive promoter. We concluded that AGF is an essential factor required for transcription of the psbD light-responsive promoter.

Research paper thumbnail of A liver-specific nuclear factor interacts with the promoter region of the large surface protein gene of human hepatitis B virus

Molecular and Cellular Biology, Nov 1, 1989

The outer envelope of the 42-nm virion of the human hepatitis B virus (HBV) is composed of the la... more The outer envelope of the 42-nm virion of the human hepatitis B virus (HBV) is composed of the large, the middle, and the major surface proteins. Whereas the middle and the major surface proteins are transcribed from the SPIH promoter of the pre-S/S gene, the large surface protein is transcribed from the SPI promoter located upstream of SPIl. We have previously shown that transcription of SPI (comprising nucleotides [nt]-380 to + 17) occurs preferentially in differentiated hepatoma cell lines (H. K. Chang and L. P. Ting, Virology 170:176-183, 1989). In this report, we further demonstrated that a sequence of 95 base pairs in the upstream region of SPI (nt-95 to +17) was necessary and sufficient for such preferential expression in differentiated hepatoma cells. By analysis of the expression of the chloramphenicol acetyltransferase gene in a series of mutants with deletions at the 5' end of SPI, we identified a positive transcriptional cis-acting element mapping at nt-95 to-72 which appears to play a key role in the regulation of the expression of the large surface protein. This region shared a high degree of sequence homology with regulatory sequences of several liver-specific genes from human, mouse, and rat, with a consensus sequence (G/A)GTTA(A/C)TNNT(C/T) NNC(A/C). We further identified a nuclear factor present in the nuclear extracts of differentiated human hepatoma cell lines which interacted specifically with this element of the SPI promoter. This nuclear factor was similar to the rat liver-specific factor HNF-1, since an oligonucleotide containing the recognition sequence of HNF-1 could efficiently compete for the human factor in a footprinting assay. The sequence at nt-93 to-68 which was bound by this factor in SPI was termed the EINF-1-binding element. Activation of the SPI promoter by human differentiated hepatocyte nuclear factor 1, described in this report, probably explains, first, the formation of the 42-nm virion specifically in liver but not in several other tissues despite the synthesis of the middle and the major surface proteins in those tissues, and second, why only differentiated hepatoma cell lines are able to produce 42-nm-like virion particles on transfection by HBV DNA.

Research paper thumbnail of Supplementary Figure legends from HMDB and 5-AzadC Combination Reverses Tumor Suppressor CCAAT/Enhancer-Binding Protein Delta to Strengthen the Death of Liver Cancer Cells

Supplementary Figure legends

Research paper thumbnail of Supplementary Method from HMDB and 5-AzadC Combination Reverses Tumor Suppressor CCAAT/Enhancer-Binding Protein Delta to Strengthen the Death of Liver Cancer Cells

Research paper thumbnail of Transcriptional regulation of precore and pregenomic RNAs of hepatitis B virus

Journal of Virology, Jul 1, 1992

Research paper thumbnail of Ribose-5-phosphate isomerase A overexpression promotes liver cancer development in transgenic zebrafish via activation of ERK and β-catenin pathways

Carcinogenesis, Nov 12, 2018

Dysregulation of the enzymes involved in the pentose phosphate pathway (PPP) is known to promote ... more Dysregulation of the enzymes involved in the pentose phosphate pathway (PPP) is known to promote tumorigenesis. Our recent study demonstrated that ribose-5-phosphate isomerase (RPIA), a key regulator of the PPP, regulates hepatoma cell proliferation and colony formation. Our studies in zebrafish reveal that RPIA-mediated hepatocarcinogenesis requires extracellular signal-regulated kinase (ERK) and β-catenin signaling. To further investigate RPIA-mediated hepatocarcinogenesis, two independent lines of transgenic zebrafish expressing human RPIA in the liver were generated. These studies reveal that RPIA overexpression triggers lipogenic factor/enzyme expression, steatosis, fibrosis and proliferation of the liver. In addition, the severity of fibrosis and the extent of proliferation are positively correlated with RPIA expression levels. Furthermore, RPIA-mediated induction of hepatocellular carcinoma (HCC) requires the ERK and β-catenin signaling pathway but is not dependent upon transaldolase levels. Our study presents a mechanism for RPIAmediated hepatocarcinogenesis and suggests that RPIA represents a valuable therapeutic target for the treatment of HCC.

Research paper thumbnail of Cytoplasmic LIF reprograms invasive mode to enhance NPC dissemination through modulating YAP1-FAK/PXN signaling

Nature Communications, Nov 30, 2018

Metastasis remains a clinically unsolved issue in nasopharyngeal carcinoma. Here, we report that ... more 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 LIF reprograms the invasive mode from collective to mesenchymal migration via acquisition of EMT and invadopodia-associated characteristics. Higher cytoplasmic LIF enhances cancer vascular dissemination and local invasion mechanistically through modulation of YAP1-FAK/PXN signaling. Immunohistochemical analyses of NPC biopsies reveal a positive correlation of cytoplasmic LIF expression with focal adhesion kinases. Pharmaceutical intervention with AZD0530 markedly reverses LIF-mediated cancer dissemination and local invasion through promotion of cytoplasmic accumulation of YAP1 and suppression of focal adhesion kinases. Given the significant role of LIF/YAP1-focal adhesion signaling in cancer dissemination, targeting of this pathway presents a promising opportunity to block metastasis.

Research paper thumbnail of Supplementary Figure 1-6 from HMDB and 5-AzadC Combination Reverses Tumor Suppressor CCAAT/Enhancer-Binding Protein Delta to Strengthen the Death of Liver Cancer Cells

Supplemental Figure 1. Anti-cancer drugs induce CEBPD expression in liver cancer cells. Supplemen... more Supplemental Figure 1. Anti-cancer drugs induce CEBPD expression in liver cancer cells. Supplemental Figure 2. Scheme of depression of epigenetic effects to enhance HMDB-induced CEBPD expression and apoptosis. Supplemental Figure 3. (Related to Figure 5) The p38/CREB pathway mediates HMDB-induced CEBPD transcriptional activation and CEBPD participates in HMDB-induced apoptosis in liver cancer cells. Supplemental Figure 4. (Related to Figure 5) Combinatorial treatment of HMDB and 5-AzadC can additively affect cell death. Supplemental Figure 5. (Related to Figure 5) Enhanced cytotoxic effects of HMDB combined with 5-AzadC on Huh7 and HepG2 cells. Supplemental Figure 6. (Related to Figure 5) Loss of CEBPD attenuated dual treatment-induced tumor killing in liver cancer cells.