YAP inactivation in estrogen receptor alpha-positive hepatocellular carcinoma with less aggressive behavior

Jeon Youngsic,Yoo Jeong Eun,Rhee Hyungjin,Kim Young-Joo,Il Kim Gwang,Chung Taek,Yoon Sarah,Shin Boram,Woo Hyun Goo,Park Young Nyun 생화학분자생물학회 2021 Experimental and molecular medicine Vol.53 No.-

The expression of estrogen receptor alpha (ERα, encoded by ESR1 ) has been shown to be associated with the prognostic outcomes of patients in various cancers; however, its prognostic and mechanistic significance in hepatocellular carcinoma (HCC) remain unclear. Here, we evaluated the expression of ERα and its association with clinicopathological features in 339 HCC patients. ERα was expressed in 9.4% (32/339) of HCCs and was related to better overall survival (OS; hazard ratio [HR] = 0.11, p = 0.009, 95% C.I. = 0.016–0.82) and disease-free survival (DFS, HR = 0.4, p = 0.013, 95% C.I. = 0.18–0.85). ERα expression was also associated with features related to more favorable prognosis, such as older age, lower serum alpha-fetoprotein level, and less microvascular invasion ( p < 0.05). In addition, to obtain mechanistic insights into the role of ERα in HCC progression, we performed integrative transcriptome data analyses, which revealed that yes-associated protein (YAP) pathway was significantly suppressed in ESR1 -expressing HCCs. By performing cell culture experiments, we validated that ERα expression enhanced YAP phosphorylation, attenuating its nuclear translocation, which in turn suppressed the downstream signaling pathways and cancer cell growth. In conclusion, we suggest that ERα expression is an indicator of more favorable prognosis in HCC and that this effect is mediated by inactivation of YAP signaling. Our results provide new clinical and pathobiological insights into ERα and YAP signaling in HCC.

Combined treatment with zingerone and its novel derivative synergistically inhibits TGF-β1 induced epithelial-mesenchymal transition, migration and invasion of human hepatocellular carcinoma cells

Kim, Young-Joo,Jeon, Youngsic,Kim, Taejung,Lim, Won-Chul,Ham, Jungyeob,Park, Young Nyun,Kim, Tae-Jin,Ko, Hyeonseok Elsevier 2017 Bioorganic & medicinal chemistry letters Vol.27 No.4

<P><B>Abstract</B></P> <P>The epithelial–mesenchymal transition (EMT) is an important cellular process during which polarized epithelial cells become motile mesenchymal cells, which promote cancer metastasis. Ginger, the rhizome of Zingiber officinale, is extensively used in cooking worldwide and also as a traditional medicinal herb with antioxidant, anti-inflammatory and anticancer properties. Several pungent compounds have been identified in ginger, including zingerone, which has anticancer potential. However, the role of zingerone in EMT is unclear. We investigated the synergistic effect of zingerone and its derivative on EMT. Transforming growth factor-beta 1 (TGF-β1) induces the EMT to promote hepatocellular carcinoma metastasis, including migration and invasion. To understand the repressive role of the combination of zingerone and its derivative (ZD 2) in hepatocellular carcinoma metastasis, we investigated the potential use of each compound of ginger, such as zingerone, ZD 2 and 6-shogaol, or the mixture of zingerone and ZD 2 (ZD 2-1) as inhibitors of TGF-β1 induced EMT development in SNU182 hepatocellular carcinoma cells <I>in vitro</I>. We show that ZD 2-1, but not zingerone, ZD 2 and 6-shogaol significantly increased expression of the epithelial marker E-cadherin and repressed Snail upregulation and expression of the mesenchymal marker N-cadherin during initiation of the TGF-β1 induced EMT. In addition, ZD 2-1 inhibited the TGF-β1 induced increase in cell migration and invasion of SNU182 hepatocellular carcinoma cells. Furthermore, ZD 2-1 significantly inhibited TGF-β1 regulated matrix metalloproteinase-2/9 and activation of Smad2/3. We also found that ZD 2-1 inhibited nuclear translocation of NF-κB, activation of p42/44 MAPK/AP1 signaling pathway in the TGF-β1 induced EMT. Our findings provide new evidence that combined treatment with ZD 2, novel zingerone derivative, and zingerone synergistically suppresses hepatocellular carcinoma metastasis <I>in vitro</I> by inhibiting the TGF-β1 induced EMT.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

The dual role of transforming growth factor-beta signatures in human B viral multistep hepatocarcinogenesis: early and late responsive genes

유정은,남지해,김영주,Youngsic Jeon,박영년 대한간암학회 2022 대한간암학회지 Vol.22 No.2

Background/Aim: Transforming growth factor-beta (TGF-β) has a dichotomous role, functioning as a tumor suppressor and tumor promoter. TGF-β signatures, explored in mouse hepatocytes, have been reported to predict the clinical outcomes of hepatocellular carcinoma (HCC) patients; HCCs exhibiting early TGF-β signatures showed a better prognosis than those with late TGF-β signatures. The expression status of early and late TGF-β signatures remains unclear in defined lesions of human B-viral multistep hepatocarcinogenesis. Methods: The expression of TGF-β signatures, early and late responsive signatures of TGF-β were investigated and analyzed for their correlation in cirrhosis, low-grade dysplastic nodules (DNs), high-grade DNs, early HCCs and progressed HCCs (pHCCs) by real-time PCR and immunohistochemistry. Results: The expression levels of TGF-β signaling genes (TGFB1, TGFBR1, TGFBR2 and SMAD4) gradually increased with the progression of hepatocarcinogenesis, peaking in pHCCs. The expression of early responsive genes of TGF-β (GADD45B, FBP1, C YP1A 2 and CYP3A4) gradually decreased, and that of the late TGF-β signatures (TWIST and SNAI1) significantly increased according to the progression of multistep hepatocarcinogenesis. Furthermore, mRNA levels of TWIST and SNAI1 were well correlated with those of stemness markers, with upregulation of TGF-β signaling, whereas FBP1 expression was inversely correlated with that of stemness markers. Conclusions: The enrichment of the late responsive signatures of TGF-β with induction of stemness is considered to be involved in the progression of the late stage of multistep hepatocarcinogenesis, whereas the early responsive signatures of TGF-β are suggested to have tumor-suppressive roles in precancerous lesions of the early stage of multistep hepatocarcinogenesis.

Eupatilin inhibits angiogenesis-mediated human hepatocellular metastasis by reducing MMP-2 and VEGF signaling

Park, Jun Yeon,Park, Do Hwi,Jeon, Youngsic,Kim, Young-Joo,Lee, Jaemin,Shin, Myoung-Sook,Kang, Ki Sung,Hwang, Gwi Seo,Kim, Hyun Young,Yamabe, Noriko Elsevier 2018 Bioorganic & medicinal chemistry letters Vol.28 No.19

<P><B>Abstract</B></P> <P>Metastasis is responsible for the great majority of deaths in cancer patients. Matrix metalloproteinases (MMPs) have critical functions in cancer metastasis. Especially, MMP-2 and MMP-9 play a major role in tumor-cell migration and invasion. Therefore, to first find out the inhibitory effect of eupatilin on expression of MMPs in SNU182 cells, we used quantitative real-rime PCR to measure MMP-2 and MMP-9 mRNA levels. Eupatilin suppressed transcription of MMP-2 in SNU182 cells more than did the corresponding controls. Also, eupatilin significantly blocked tube formation when treated with a concentration of 3.125 or 6.25 μg/mL on human umbilical vein vascular endothelial cells (HUVECs). Eupatilin induced significant anti-angiogenic potential associated with down-regulation of hypoxia-inducible factor 1-alpha (HIF-1α), vascular endothelial growth factor (VEGF), and phosphorylated Akt expression. Thus, tube-formation inhibition and MMP-2-mediated migration are likely to be important therapeutic targets of eupatilin in hepatocellular carcinoma metastasis.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Eupatilin inhibits human hepatocellular metastasis. </LI> <LI> HIF-1α is important therapeutic targets of eupatilin. </LI> <LI> Eupatilin inhibits angiogenesis in HUVECs. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Suppression of PROX1‐mediated TERT expression in hepatitis B viral hepatocellular carcinoma

Kim, Young‐,Joo,Yoo, Jeong Eun,Jeon, Youngsic,Chong, Jae Uk,Choi, Gi Hong,Song, Dae‐,Geun,Jung, Sang Hoon,Oh, Bong‐,Kyeong,Park, Young Nyun Alan R. Liss, Inc 2018 International journal of cancer Vol.143 No.12

<P>Somatic mutations in the telomerase reverse transcriptase (<I>TERT</I>) promoter are related to telomerase activation and frequently occur at two hot spots located at −124 and −146 bp relative to the start codon in various cancers. Here, we investigated the occurrence and implications of genetic alterations in the <I>TERT</I> promoter in hepatitis B viral hepatocellular carcinoma (B viral HCC). <I>TERT</I> promoter mutations, especially −124C>T, clearly enhanced transcriptional activity in HCC cell lines. In contrast, <I>TERT</I> mRNA expression was lower in B viral HCC patients with <I>TERT</I> promoter mutations than in those without. We identified prospero homeobox protein 1 (PROX1) as a novel transcriptional activator of <I>TERT</I>; this protein was shown to have particularly strong binding affinity for the mutant <I>TERT</I> promoter. However, stable expression of the hepatitis B virus X (HBx) protein inhibited PROX1‐mediated <I>TERT</I> expression <I>in vitro.</I> Our data suggest that <I>TERT</I> promoter mutations can enhance the promoter activity in HCC cell lines expressing <I>PROX1</I> but are not the predominant mechanism of <I>TERT</I> upregulation in B viral HCC patients, based on the inhibition of PROX1‐dependent transcriptional activation by HBx.</P>

SEQprocess: a modularized and customizable pipeline framework for NGS processing in R package

Joo, Taewoon,Choi, Ji-Hye,Lee, Ji-Hye,Park, So Eun,Jeon, Youngsic,Jung, Sae Hoon,Woo, Hyun Goo BioMed Central 2019 BMC bioinformatics Vol.20 No.-

<P><B>Backgrounds</B></P><P>Next-Generation Sequencing (NGS) is now widely used in biomedical research for various applications. Processing of NGS data requires multiple programs and customization of the processing pipelines according to the data platforms. However, rapid progress of the NGS applications and processing methods urgently require prompt update of the pipelines. Recent clinical applications of NGS technology such as cell-free DNA, cancer panel, or exosomal RNA sequencing data also require appropriate customization of the processing pipelines. Here, we developed SEQprocess, a highly extendable framework that can provide standard as well as customized pipelines for NGS data processing.</P><P><B>Results</B></P><P>SEQprocess was implemented in an R package with fully modularized steps for data processing that can be easily customized. Currently, six pre-customized pipelines are provided that can be easily executed by non-experts such as biomedical scientists, including the National Cancer Institute’s (NCI) Genomic Data Commons (GDC) pipelines as well as the popularly used pipelines for variant calling (e.g., GATK) and estimation of allele frequency, RNA abundance (e.g., TopHat2/Cufflink), or DNA copy numbers (e.g., Sequenza). In addition, optimized pipelines for the clinical sequencing from cell-free DNA or miR-Seq are also provided. The processed data were transformed into R package-compatible data type ‘ExpressionSet’ or ‘SummarizedExperiment’, which could facilitate subsequent data analysis within R environment. Finally, an automated report summarizing the processing steps are also provided to ensure reproducibility of the NGS data analysis.</P><P><B>Conclusion</B></P><P>SEQprocess provides a highly extendable and R compatible framework that can manage customized and reproducible pipelines for handling multiple legacy NGS processing tools.</P>

Dendrobium moniliforme attenuates high-fat diet-induced renal damage in mice through the regulation of lipid-induced oxidative stress.

Lee, Woojung,Eom, Dae-Woon,Jung, Yujung,Yamabe, Noriko,Lee, Seungyong,Jeon, Youngsic,Hwang, Ye Ran,Lee, Ji Hwan,Kim, Yong Kee,Kang, Ki Sung,Kim, Su-Nam Institute for Advanced Research in Asian Science a 2012 The American journal of Chinese medicine Vol.40 No.6

<P>Obesity is an important and preventable risk factor for renal disease. The administration of an antioxidant with a lipid-lowering effect is an important therapeutic approach for kidney disease in obese patients. The present study was conducted to examine whether methanolic extract of Dendrobium moniliforme (DM), one of the most famous traditional medicines used in many parts of the world, has an antioxidant effect in vitro and an ameliorative effect on high-fat diet (HFD)-induced alterations such as renal dysfunction and lipid accumulation in vivo. The 1,1-diphenyl-2-picrylhydrazyl radical scavenging activity of DM extract (IC(50) = 29.6 μg/mL) was increased in a dose-dependent manner. The LLC-PK1 kidney cell damage induced by oxidative stress was significantly inhibited by the treatments with DM extract. In the animal study, DM extract (200 mg/kg) was orally administered every day for nine weeks to HFD-fed mice, and its effect was compared with that of metformin. The administration of DM extract decreased the elevated serum glucose, total cholesterol concentration and renal lipid accumulation in HFD-fed mice. It also ameliorated renal dysfunction biomarkers including serum creatinine and renal collagen IV deposition. Taken together, these results provide important evidence that DM extract exhibits a pleiotropic effect on obesity induced parameters and exerted a renoprotective effect in HFD-fed mice.</P>

Increased Expression of the Matrix-Modifying Enzyme Lysyl Oxidase-Like 2 in Aggressive Hepatocellular Carcinoma with Poor Prognosis

Jiwoon Choi,Taek Chung,Hyungjin Rhee,Young-Joo Kim,Youngsic Jeon,Jeong Eun Yoo,Songmi Noh,Dai Hoon Han,Young Nyun Park 거트앤리버 소화기연관학회협의회 2019 Gut and Liver Vol.13 No.1

Background/Aims: Lysyl oxidase-like 2 (LOXL2), a collagenmodifying enzyme, has been implicated in cancer invasiveness and metastasis. Methods: We evaluated the expression of LOXL2 protein, in addition to carbonic anhydrase IX (CAIX), keratin 19, epithelial cell adhesion molecule, and interleukin 6, in 105 resected hepatocellular carcinomas (HCCs) by immunohistochemistry. Results: LOXL2 positivity was found in 14.3% (15/105) of HCCs, and it was significantly associated with high serum α-fetoprotein levels, poor differentiation, fibrous stroma, portal vein invasion, and advanced TNM stage (p<0.05 for all). Additionally, LOXL2 positivity was significantly associated with CAIX (p=0.005) and stromal interleukin 6 expression (p=0.001). Survival analysis of 99 HCC patients revealed LOXL2 positivity to be a poor prognostic factor; its prognostic impact appeared in progressed HCCs. Furthermore, LOXL2 positivity was shown to be an independent predictor of overall survival and disease-specific survival (p<0.05 for all). Interestingly, co-expression of LOXL2 and CAIX was also an independent predictor for overall survival, disease-specific survival, disease-free survival, and extrahepatic recurrence-free survival (p<0.05 for all). Conclusions: LOXL2 expression represents a subgroup of HCCs with more aggressive behavior and is suggested to be a poor prognostic marker in HCC patients.

Dynamics of Genomic, Epigenomic, and Transcriptomic Aberrations during Stepwise Hepatocarcinogenesis

Jee, Byul A,Choi, Ji-Hye,Rhee, Hyungjin,Yoon, Sarah,Kwon, So Mee,Nahm, Ji Hae,Yoo, Jeong Eun,Jeon, Youngsic,Choi, Gi Hong,Woo, Hyun Goo,Park, Young Nyun American Association for Cancer Research 2019 Cancer Research Vol.79 No.21

<P>Multiomics profiling and integrative analyses of stepwise hepatocarcinogenesis reveal novel mechanistic and clinical insights into hepatocarcinogenesis.</P><P><B></B></P><P>Hepatocellular carcinoma (HCC) undergoes a stepwise progression from liver cirrhosis to low-grade dysplastic nodule (LGDN), high-grade dysplastic nodule (HGDN), early HCC (eHCC), and progressed HCC (pHCC). Here, we profiled multilayered genomic, epigenomic, and transcriptomic aberrations in the stepwise hepatocarcinogenesis. Initial DNA methylation was observed in eHCC (e.g., <I>DKK3, SALL3</I>, and <I>SOX1</I>) while more extensive methylation was observed in pHCC. In addition, eHCCs showed an initial loss of DNA copy numbers of tumor suppressor genes in the 4q and 13q regions, thereby conferring survival benefits to cancer cells. Transcriptome analysis revealed that HGDNs expressed endoplasmic reticulum (ER) stress–related genes, while eHCC started to express oncogenes. Furthermore, integrative analysis indicated that expression of the serine peptidase inhibitor, Kazal type 1 (SPINK1), played a pivotal role in eHCC development. Significant demethylation of SPINK1 was observed in eHCC compared to HGDN. The study also demonstrated that ER stress may induce SPINK1 demethylation and expression in liver cancer cells. In conclusion, these results reveal the dynamics of multiomic aberrations during malignant conversion of liver cancer, thus providing novel pathobiological insights into hepatocarcinogenesis.</P><P><B>Significance:</B></P><P>Multiomics profiling and integrative analyses of stepwise hepatocarcinogenesis reveal novel mechanistic and clinical insights into hepatocarcinogenesis.</P>

Protective Effect of Esculin on Streptozotocin-Induced Diabetic Renal Damage in Mice

Kang, Ki Sung,Lee, Woojung,Jung, Yujung,Lee, Ji Hwan,Lee, Seungyong,Eom, Dae-Woon,Jeon, Youngsic,Yoo, Hye Hyun,Jin, Ming Ji,Song, Kyung Il,Kim, Won Jun,Ham, Jungyeob,Kim, Hyoung Ja,Kim, Su-Nam American Chemical Society 2014 Journal of agricultural and food chemistry Vol.62 No.9

<P>The present study investigated the presence and mechanism of esculin-mediated renoprotection to assess its therapeutic potential. Esculin was orally administered at 20 mg/kg/day for 2 weeks to streptozotocin-induced diabetic mice, and its effects were compared with those of the vehicle in normal and diabetic mice. After oral administration of esculin to mice, the concentrations of esculin and esculetin in blood were 159.5 ± 29.8 and 9.7 ± 4.9 ng/mL at 30 min, respectively. Food and water intake were significantly increased in the diabetic mice compared to normal mice but attenuated in mice receiving esculin. The elevated blood glucose level and hepatic glucose-6-phosphatase expression were significantly reduced in esculin-treated diabetic mice, supporting the antidiabetic effect of esculin. Esculin also increased the uptake of glucose and induced the insulin-evoked phosphorylation of insulin receptor, Akt, and glycogen synthase kinase 3β in C2C12 myotubes, indicating a potential for improvement of insulin sensitivity. In addition, esculin lessened the elevated blood creatinine levels in diabetic mice and ameliorated diabetes-induced renal dysfunction by reducing caspase-3 activation in the kidney. Data support the beneficial effect of esculin against diabetes and oxidative stress-related inflammatory processes in the kidney.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jafcau/2014/jafcau.2014.62.issue-9/jf403840c/production/images/medium/jf-2013-03840c_0008.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/jf403840c'>ACS Electronic Supporting Info</A></P>