Gene Microarray Assessment of Multiple Genes and Signal Pathways Involved in Androgen-dependent Prostate Cancer Becoming Androgen Independent

Liu, Jun-Bao,Dai, Chun-Mei,Su, Xiao-Yun,Cao, Lu,Qin, Rui,Kong, Qing-Bo Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.22

To study the gene expression change and possible signal pathway during androgen-dependent prostate cancer (ADPC) becoming androgen-independent prostate cancer (AIPC), an LNCaP cell model of AIPC was established using flutamide in combination with androgen-free environment inducement, and differential expression genes were screened by microarray. Then the biological process, molecular function and KEGG pathway of differential expression genes are analyzed by Molecule Annotation System (MAS). By comparison of 12,207 expression genes, 347 expression genes were acquired, of which 156 were up-ragulated and 191 down-regulated. After analyzing the biological process and molecule function of differential expression genes, these genes are found to play crucial roles in cell proliferation, differntiation, cell cycle control, protein metabolism and modification and other biological process, serve as signal molecules, enzymes, peptide hormones, cytokines, cytoskeletal proteins and adhesion molecules. The analysis of KEGG show that the relevant genes of AIPC transformation participate in glutathione metabolism, cell cycle, P53 signal pathway, cytochrome P450 metabolism, Hedgehog signal pathway, MAPK signal pathway, adipocytokines signal pathway, PPAR signal pathway, TGF-${\beta}$ signal pathway and JAK-STAT signal pathway. In conclusion, during the process of ADPC becoming AIPC, it is not only one specific gene or pathway, but multiple genes and pathways that change. The findings above lay the foundation for study of AIPC mechanism and development of AIPC targeting drugs.

VCAN activates JAK/STAT signaling pathway to promote the progression of LPS-induced acute pneumonia

He Yuqin,Mao Junqian 대한독성 유전단백체 학회 2024 Molecular & cellular toxicology Vol.20 No.3

Background Pneumonia is a lower respiratory tract disease induced by pathogens and is related to the inflammatory stimulation by endotoxin from microorganisms. Objective This study aimed to investigate the effects and potential mechanism of action of versican (VCAN) in pneumonia. Methods A mouse model of pneumonia was established using a nasopharyngeal drip containing lipopolysaccharide (LPS). VCAN mRNA and versican protein levels in lung tissues were evaluated by qRT-PCR, western blotting, and immunohistochemistry. Injury and apoptosis in the lung tissue were observed using H&E and TUNEL staining, respectively. The W/D ratio was used to evaluate pulmonary edema. The inflammation levels in the BALF were assayed by ELISA. The signaling pathways regulated by VCAN were analyzed by GSEA. In addition, the role of VCAN in vitro was confirmed in LPS-stimulated ACEs. Cell viability, apoptosis, inflammation, and related proteins were measured by CCK-8 assay, flow cytometry, ELISA, and western blotting, respectively. VCAN mRNA and versican protein levels were significantly increased in the lung tissues of mice with pneumonia. Results VCAN shRNA significantly alleviated pulmonary edema, apoptosis, and lung tissue injury. VCAN shRNA reduced inflammation levels in the BALF. Furthermore, VCAN activated the JAK/STAT signaling pathway. VCAN shRNA markedly suppressed expression of proteins of the JAK/STAT signaling pathway in lung tissues. In addition, VCAN siRNA increased cell viability, decreased apoptosis, reduced inflammation and inhibited the JAK/STAT signaling pathway in LPS-stimulated ACEs. The effect of co-treatment with VCAN siRNA and the JAK1/2 inhibitor ruxolitinib (Rux) on LPS-stimulated ACEs was similar to that of Rux treatment alone. Conclusions VCAN knockdown alleviates lung injury of mice with pneumonia by inhibiting the JAK/STAT signaling pathway. Background Pneumonia is a lower respiratory tract disease induced by pathogens and is related to the inflammatory stimulation by endotoxin from microorganisms. Objective This study aimed to investigate the effects and potential mechanism of action of versican (VCAN) in pneumonia. Methods A mouse model of pneumonia was established using a nasopharyngeal drip containing lipopolysaccharide (LPS). VCAN mRNA and versican protein levels in lung tissues were evaluated by qRT-PCR, western blotting, and immunohistochemistry. Injury and apoptosis in the lung tissue were observed using H&E and TUNEL staining, respectively. The W/D ratio was used to evaluate pulmonary edema. The inflammation levels in the BALF were assayed by ELISA. The signaling pathways regulated by VCAN were analyzed by GSEA. In addition, the role of VCAN in vitro was confirmed in LPS-stimulated ACEs. Cell viability, apoptosis, inflammation, and related proteins were measured by CCK-8 assay, flow cytometry, ELISA, and western blotting, respectively. VCAN mRNA and versican protein levels were significantly increased in the lung tissues of mice with pneumonia. Results VCAN shRNA significantly alleviated pulmonary edema, apoptosis, and lung tissue injury. VCAN shRNA reduced inflammation levels in the BALF. Furthermore, VCAN activated the JAK/STAT signaling pathway. VCAN shRNA markedly suppressed expression of proteins of the JAK/STAT signaling pathway in lung tissues. In addition, VCAN siRNA increased cell viability, decreased apoptosis, reduced inflammation and inhibited the JAK/STAT signaling pathway in LPS-stimulated ACEs. The effect of co-treatment with VCAN siRNA and the JAK1/2 inhibitor ruxolitinib (Rux) on LPS-stimulated ACEs was similar to that of Rux treatment alone. Conclusions VCAN knockdown alleviates lung injury of mice with pneumonia by inhibiting the JAK/STAT signaling pathway.

어류신경괴사증바이러스(nervous necrosis virus, NNV) 감염에 따른 숙주의 방어기전관련 세포신호전달

김종오(Jong-Oh Kim) 한국생명과학회 2020 생명과학회지 Vol.30 No.4

신경괴사증바이러스(NNV)는 25 nm의 작은 입자 크기에 RNA1 (3.4 kb, RdRp), RNA2 (1.4 kb, capsid protein) 두 가닥의 RNA를 유전정보를 가진다. NNV는 1980년대 말 처음 보고된 이후 전 세계적으로 120여종의 어류에 감염을 일으키며 심각한 피해를 일으키고 있는 바이러스이다. NNV 감염에 의한 피해를 최소화하고 효율적인 백신들을 개발하기 위해서는 무엇보다 NNV 감염에 따른 세포내 신호전달체계를 이해할 필요가 있다. NNV는 세포 내 감염 이후 숙주가 가진 바이러스 복제에 필요한 요소들을 이용할 수 있도록 숙주세포의 cell cycle arrest 등의 기작을 이용하는 것으로 알려졌다. 반면에 숙주 세포는 NNV와 감염된 세포를 제어하기 위해 RIG-1-like receptor signaling pathway 등을 통해 NNV 감염을 인지한 다음 IFN signaling pathway를 통해 항바이러스 작용에 필요한 ISG들을 발현시킨다. 또한 감염된 세포들을 사멸시키기 위해 ER stress를 통한 unfolded protein response (UPR), mitochondria-mediated cell death 작용을 통해 감염된 세포의 apoptosis를 유발한다. NNV 감염 기작에 대한 세포신호전달연구는 아직 초기단계이며 검증해야 할 pathway들이 아직도 많이 남아있는 상황이다. 따라서 NNV 감염과 연관된 다양한 세포신호전달체계를 탐색하고 질병 특이적인 세포신호전달체계를 이해함으로써 신속하고 정확한 진단법 및 백신 개발에 많은 도움이 될 것으로 생각된다. Nervous necrosis virus (NNV) contains a bi-segmented viral genome, RNA1 (3.4 kb, RdRp), and RNA2 (1.4 kb, capsid protein) in a small particle (25 nm). Despite its extremely compact size, NNV has caused serious damage by infecting approximately 120 fish species worldwide since it was first reported in the late 1980s. In order to minimize the damage caused by NNV infection and develop effective vaccines, it is necessary to understand the intra cellular signaling system according to NNV infection. NNV infection induces cell cycle arrest at the G1 phase via the p53-dependent pathway to use the cellular system for its replication. Otherwise, host cells recognize NNV infection through the RIG-1-like receptor (RLR) signaling pathway to control the virus and infected cells, and then ISGs required for antiviral action are activated via the IFN signaling pathway. Moreover, apoptosis of infected cells is triggered by the unfolded protein response (UPR) through ER stress and mitochondria-mediated cell death. Cell signaling studies on the NNV infection mechanisms are still at an early stage and many pathways have yet to be identified. Understanding the various disease-specific cellular signaling systems associated with NNV infection is essential for rapid and accurate diagnosis and vaccine development.

Oncogenic Signaling Pathways in The Cancer Genome Atlas

Sanchez-Vega, Francisco,Mina, Marco,Armenia, Joshua,Chatila, Walid K.,Luna, Augustin,La, Konnor C.,Dimitriadoy, Sofia,Liu, David L.,Kantheti, Havish S.,Saghafinia, Sadegh,Chakravarty, Debyani,Daian, F Elsevier 2018 Cell Vol.173 No.2

<P><B>Summary</B></P> <P>Genetic alterations in signaling pathways that control cell-cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), we analyzed the mechanisms and patterns of somatic alterations in ten canonical pathways: cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGFβ signaling, p53 and β-catenin/Wnt. We charted the detailed landscape of pathway alterations in 33 cancer types, stratified into 64 subtypes, and identified patterns of co-occurrence and mutual exclusivity. Eighty-nine percent of tumors had at least one driver alteration in these pathways, and 57% percent of tumors had at least one alteration potentially targetable by currently available drugs. Thirty percent of tumors had multiple targetable alterations, indicating opportunities for combination therapy.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Alteration map of 10 signaling pathways across 9,125 samples from 33 cancer types </LI> <LI> Reusable, curated pathway templates that include a catalogue of driver genes </LI> <LI> 57% of tumors have at least one potentially actionable alteration in these pathways </LI> <LI> Co-occurrence of actionable alterations suggests combination therapy opportunities </LI> </UL> </P> <P><B>Graphical Abstract</B></P> <P>[DISPLAY OMISSION]</P>

Inhibition of the interaction between Hippo/YAP and Akt signaling with ursolic acid and 3′3-diindolylmethane suppresses esophageal cancer tumorigenesis

Ruo Yu Meng,Cong Shan Li,Dan Hu,Soon-Gu Kwon,Hua Jin,Ok Hee Chai,Ju-Seog Lee,김수미 대한약리학회 2023 The Korean Journal of Physiology & Pharmacology Vol.27 No.5

Hippo/YAP signaling hinders cancer progression. Inactivation of this pathway contributes to the development of esophageal cancer by activation of Akt. However, the possible interaction between Akt and Hippo/YAP pathways in esophageal cancer progression is unclear. In this study, we found that ursolic acid (UA) plus 3′3-diindolylmethane (DIM) efficiently suppressed the oncogenic Akt/Gsk-3β signaling pathway while activating the Hippo tumor suppressor pathway in esophageal cancer cells. Moreover, the addition of the Akt inhibitor LY294002 and the PI3K inhibitor 3-methyladenine enhanced the inhibitory effects of UA plus DIM on Akt pathway activation and further stimulated the Hippo pathway, including the suppression of YAP nuclear translocation in esophageal cancer cells. Silencing YAP under UA plus DIM conditions significantly increased the activation of the tumor suppressor PTEN in esophageal cancer cells, while decreasing p-Akt activation, indicating that the Akt signaling pathway could be down-regulated in esophageal cancer cells by targeting PTEN. Furthermore, in a xenograft nude mice model, UA plus DIM treatment effectively diminished esophageal tumors by inactivating the Akt pathway and stimulating the Hippo signaling pathway. Thus, our study highlights a feedback loop between the PI3K/Akt and Hippo signaling pathways in esophageal cancer cells, implying that a low dose of UA plus DIM could serve as a promising chemotherapeutic combination strategy in the treatment of esophageal cancer.

Candida albicans의 형태변환 조절과정 규명의 최근 연구 동향

박윤희,박희문 충남대학교 생물공학연구소 2009 생물공학연구지 Vol.15 No.-

The opportunistic fungal pathogen Candida albicans can grow as yeast, pseudohyphae or true hyphae, and morphology of each cell is essential for efficient dissemination and tissue invasion. Therefore the ability to switch in C. albicans is thought to be an important virulence factor. The morphological conversion of C. albicans can be triggered in vitro by a various environmental stimuli including serum, pH, temperature, and nutrient depletion. These inducers regulate the expression of hypha-specific genes, which are involved in morphogenesis, through multiple signaling pathways such as MAPK pathway and cAMP/PKA pathway. In order to investigate Signal transduction pathways, disruption or over-expression of the component gene(s) were performed and then change(s) in morphological transition as well as the expression of hypha-specific genes are observed in general. As the approach to unravel new roles of already-known signaling pathways in fungal pathogenicity, responses toward external stimuli such as hypoxic condition and iron utilization are performed these days. The new approaches revealed that the morphological conversion in C. albicans is resulted from the consorted action of multiple signaling pathways rather than from a single pathway. Consequently, the existence of a novel Signaling pathway for dimorphic switch in C. albicans could not be excluded. In this context, it is noteworthy that the involvement of LAMMER kinase in fungal development; LAMMER kinase is known to be involved in oxidative-stress response, filamentous growth, and flocculation in fission yeast; S. cerevisiae LAMMER kinase, ScKNS1, is also reported to phosphorylate Slt2, MAPK of cell wall integrity pathway, and to interact with dual-specificity phosphatase Sdp1, which regulates the activity of Slt2. Therefore, studies on the function of LAMMER kinase in C. albicans will be helpful to reveal novel regulatory mechanisms for virulence in pathogenic fungi.

Transcriptional Properties of the BMP, $TGF-\beta$, RTK, Wnt, Hh, Notch, and JAK/STAT Signaling Molecules in Mouse Embryonic Stem Cells

Rho Jeung-Yon,Bae Gab-Yong,Chae Jung-Il,Yu Kweon,Koo Deog-Bon,Lee Kyung-Kwang,Han Yong-Mahn The Korean Society of Animal Reproduction 2006 Reproductive & developmental biology Vol.30 No.2

Major characteristics of embryonic stem cells (ESCs) are sustaining of sternness and pluripotency by self-renewal. In this report, transcriptional profiles of the molecules in the developmentally important signaling pathways including Wnt, BMP4, $TGF-\beta$, RTK, Hh, Notch, and JAK/STAT signaling pathways were investigated to understand the self-renewal of mouse ESCs (mESCs), J1 line, and compared with the NIH3T3 cell line and mouse embryonic fibroblast (MEF) cells as controls. In the Wnt signaling pathway, the expression of Wnt3 was seen widely in mESCs, suggesting that the ligand may be an important regulator for self-renewal in mESCs. In the Hh signaling pathway, the expression of Gli and N-myc were observed extensively in mESCs, whereas the expression levels of in a Shh was low, suggesting that intracellular molecules may be essential for the self-renewal of mESCs. IGF-I, IGF-II, IGF-IR and IGF-IIR of RTK signaling showed a lower expression in mESCs, these molecules related to embryo development may be restrained in mESCs. The expression levels of the Delta and HESS in Notch signaling were enriched in mESCs. The expression of the molecules related to BMP and JAK-STAT signaling pathways were similar or at a slightly lower level in mESCs compared to those in MEF and NIH3T3 cells. It is suggested that the observed differences in gene expression profiles among the signaling pathways may contribute to the self-renewal and differentiation of mESCs in a signaling-specific manner.

Transcriptional Properties of the BMP, TGF-B, RTK, Wnt, Hh, Notch, and JAK/STAT Signaling Molecules in Mouse Embryonic Stem Cells

Jeung-Yon Rho,Gab-Yong Bae,Jung-Il Chae,Kweon Yu,Deog-Bon Koo,Kyung-Kwang Lee,Yong-Mahn Han 한국동물생명공학회(구 한국동물번식학회) 2006 Reproductive & developmental biology Vol.30 No.2

Major characteristics of embryonic stem cells (ESCs) are sustaining of stemness and pluripotency by self-renewal. In this report, transcriptional profiles of the molecules in the developmentally important signaling pathways including Wnt, BMP4, TGF-β, RTK, Hh, Notch, and JAK/STAT signaling pathways were investigated to understand the self- renewal of mouse ESCs (mESCs), J1 line, and compared with the NIH3T3 cell line and mouse embryonic fibroblast (MEF) cells as controls. In the Wnt signaling pathway, the expression of Wnt3 was seen widely in mESCs, suggesting that the ligand may be an important regulator for self-renewal in mESCs. In the Hh signaling pathway, the expression of Gli and N-myc were observed extensively in mESCs, whereas the expression levels of in a Shh was low, suggesting that intracellular molecules may be essential for the self-renewal of mESCs. IGF-I, IGF-II, IGF-IR and IGF-IIR of RTK signaling showed a lower expression in mESCs, these molecules related to embryo development may be restrained in mESCs. The expression levels of the Delta and HES5 in Notch signaling were enriched in mESCs. The expression of the molecules related to BMP and JAK-STAT signaling pathways were similar or at a slightly lower level in mESCs compared to those in MEF and NIH3T3 cells. It is suggested that the observed differences in gene expression profiles among the signaling pathways may contribute to the self-renewal and differentiation of mESCs in a signaling-specific manner.

Role of MAPK Signaling Pathways in Regulating the Hydrophobin Cryparin in the Chestnut Blight Fungus Cryphonectria parasitica

( Kum-kang So ),( Dae-hyuk Kim ) 한국균학회 2017 Mycobiology Vol.45 No.4

We assessed the regulation of cryparin, a class II hydrophobin, using three representative mitogen-activated protein kinase (MAPK) pathways in Cryphonectria parasitica. Mutation of the CpSlt2 gene, an ortholog of yeast SLT2 in the cell wall integrity (CWI) pathway, resulted in a dramatic decrease in cryparin production. Similarly, a mutant of the CpBck1 gene, a MAP kinase kinase kinase gene in the CWI pathway, showed decreased cryparin production. Additionally, mutation of the cpmk1 gene, an ortholog of yeast HOG1, showed decreased cryparin production. However, mutation of the cpmk2 gene, an ortholog of yeast Kss1/Fus3, showed increased cryparin production. The easy-wet phenotype and accumulation of the cryparin transcript in corresponding mutants were consistent with the cryparin production results. In silico analysis of the promoter region of the cryparin gene revealed the presence of binding motifs related to downstream transcription factors of CWI, HOG1, and pheromone responsive pathways including MADS-box- and Ste12-binding domains. Real-time reverse transcriptase PCR analyses indicated that both CpRlm1, an ortholog of yeast RLM1 in the CWI pathway, and cpst12, an ortholog of yeast STE12 in the mating pathway, showed significantly reduced transcription levels in the mutant strains showing lower cryparin production in C. prasitica. However, the transcription of CpMcm1, an ortholog of yeast MCM1, did not correlate with that of the mutant strains showing downregulation of cryparin. These results indicate that three representative MAPK pathways played a role in regulating cryparin production. However, regulation varied depending on the MAPK pathways: the CWI and HOG1 pathways were stimulatory, whereas the pheromone-responsive MAPK was repressive.

마취통증의학과 영역에서 Intra-cellular Signaling Pathway의 이용

주진덕 ( Jin Deok Joo ) 대한마취과학회 2009 Korean Journal of Anesthesiology Vol.57 No.3

At the level of individual cells, signaling is crucial in cell division, differentiation, metabolic control and death. Reception of the signals depends on receptor proteins that are usually at the cell surface, and these receptor proteins bind the signal molecule. The binding activates the receptor, which in turn activates one or more of the intra-cellular signaling pathways. These relay chains of molecules, mainly intra-cellular signaling proteins, process the signal inside the receiving cell and distribute it to the appropriate intra-cellular targets. Cell signaling pathways are involved in the pathophysiology of many diseases and also in the mechanisms of action of many drugs, including local and general anesthetics. Knowledge of the basic cell signaling mechanisms is essential for understanding many of the pathophysiologic and pharmacologic mechanisms. Therefore, if we focus on applying the new cellular and molecular biologic research, these efforts could identify the mechanism of diseases and help develop new drugs in the field of anesthesiology and pain medicine. (Korean J Anesthesiol 2009;57:277∼83)