Genomic Predictors for Recurrence Patterns of Hepatocellular Carcinoma: Model Derivation and Validation

Kim, Ji Hoon,Sohn, Bo Hwa,Lee, Hyun-Sung,Kim, Sang-Bae,Yoo, Jeong Eun,Park, Yun-Yong,Jeong, Woojin,Lee, Sung Sook,Park, Eun Sung,Kaseb, Ahmed,Kim, Baek Hui,Kim, Wan Bae,Yeon, Jong Eun,Byun, Kwan Soo,C Public Library of Science 2014 PLoS medicine Vol.11 No.12

<▼1><P>In this study, Lee and colleagues develop a genomic predictor that can identify patients at high risk for late recurrence of hepatocellular carcinoma (HCC) and provided new biomarkers for risk stratification.</P></▼1><▼2><P><B>Background</B></P><P>Typically observed at 2 y after surgical resection, late recurrence is a major challenge in the management of hepatocellular carcinoma (HCC). We aimed to develop a genomic predictor that can identify patients at high risk for late recurrence and assess its clinical implications.</P><P><B>Methods and Findings</B></P><P>Systematic analysis of gene expression data from human liver undergoing hepatic injury and regeneration revealed a 233-gene signature that was significantly associated with late recurrence of HCC. Using this signature, we developed a prognostic predictor that can identify patients at high risk of late recurrence, and tested and validated the robustness of the predictor in patients (<I>n = </I>396) who underwent surgery between 1990 and 2011 at four centers (210 recurrences during a median of 3.7 y of follow-up). In multivariate analysis, this signature was the strongest risk factor for late recurrence (hazard ratio, 2.2; 95% confidence interval, 1.3–3.7; <I>p</I> = 0.002). In contrast, our previously developed tumor-derived 65-gene risk score was significantly associated with early recurrence (<I>p</I> = 0.005) but not with late recurrence (<I>p</I> = 0.7). In multivariate analysis, the 65-gene risk score was the strongest risk factor for very early recurrence (<1 y after surgical resection) (hazard ratio, 1.7; 95% confidence interval, 1.1–2.6; <I>p</I> = 0.01). The potential significance of <I>STAT3</I> activation in late recurrence was predicted by gene network analysis and validated later. We also developed and validated 4- and 20-gene predictors from the full 233-gene predictor. The main limitation of the study is that most of the patients in our study were hepatitis B virus–positive. Further investigations are needed to test our prediction models in patients with different etiologies of HCC, such as hepatitis C virus.</P><P><B>Conclusions</B></P><P>Two independently developed predictors reflected well the differences between early and late recurrence of HCC at the molecular level and provided new biomarkers for risk stratification.</P><P><I>Please see later in the article for the Editors' Summary</I></P></▼2><▼3><P><B>Editors' Summary</B></P><P><B>Background</B></P><P>Primary liver cancer—a tumor that starts when a liver cell acquires genetic changes that allow it to grow uncontrollably—is the second-leading cause of cancer-related deaths worldwide, killing more than 600,000 people annually. If hepatocellular cancer (HCC; the most common type of liver cancer) is diagnosed in its early stages, it can be treated by surgically removing part of the liver (resection), by liver transplantation, or by local ablation, which uses an electric current to destroy the cancer cells. Unfortunately, the symptoms of HCC, which include weight loss, tiredness, and jaundice (yellowing of the skin and eyes), are vague and rarely appear until the cancer has spread throughout the liver. Consequently, HCC is rarely diagnosed before the cancer is advanced and untreatable, and has a poor prognosis (likely outcome)—fewer than 5% of patients survive for five or more years after diagnosis. The exact cause of HCC is unclear, but chronic liver (hepatic) injury and inflammation (caused, for example, by infection with hepatitis B virus [HBV] or by alcohol abuse) promote tumor development.</P><P><B>Why Was This Study Done?</B></P><P>Even when it is diagnosed early, HCC has a poor prognosis because it often recurs. Patients treated for HCC can experience two distinct types of tumor recurrence. Early recurrence, which usually happens within the first two years after surg

Use of Real-Time Quantitative PCR to Identify High Expressed Genes in Head and Neck Squamous Cell Carcinoma Cell Lines

Yong-Gyoo Lee,So-Young Chun,Hae-Ahm Lee,Yoon-Kyung Sohn,Ku-Seong Kang,Joung-Ok Kim,Sang-Mo Yun,Jung-Wan Kim,Hyun-Jung Jang 대한구강악안면외과학회 2006 대한구강악안면외과학회지 Vol.32 No.1

Head and neck squamous cell carcinoma(HNSCC) is the sixth most common cancer among men in the developed world affecting the tongue, pharynx, larynx and oral cavity. HNSCC is thought to represent a multistep process whereby carcinogen exposure leads to genetic instability in the tissue and accumulation of specific genetic events, which result in dysregulation of proliferation, differentiation, and cell loss and the acquisition of invasive capacity. Despite therapeutic and diagnostic progress in oncology during the past decades, the prognosis of HNSCC remains poor. Thus it seems that finding a biological tumor markers which will increase the early diagnosis and treatment monitoring rates, is of paramount importance in respect to improving prognosis. In an effort to identify gene expression signatures that may serve as biomarkers, this study several genes were selected, such as H3,3A, S100A7, UCHL1, GSTP1, PAI-2, PLK, TGFβ1 and bFGF, and used 7 HNSCC cell lines that were established various anatomical sites, and also 17 other cancer cell lines were used for control group using real-time quantitative RT-PCR and immunocytochemical analysis with a monoclonal antibody. In this study, S100A7 showed a clearly restricted occurrence in tongue originated cell line, and GSTP1 expression level in the pharynx originated cell line was very increased, relative to corresponding other cell lines. These results suggest that S100A7 and GSTP1 genes’ expression can occur during tongue and pharynx originated head and neck tumorigenesis and that genetic change is an important driving force in the carcinogenesis process. This data indicate that S100A7 and GSTP1 expression pattern in HNSCC reflect both diagnostic clue and biological marker. And this is provides a foundation for the development of site-specific diagnostic strategies and treatments for HNSCC.

Consensus molecular subtypes reflecting distinct clinical phenotypes of hepatocellular carcinoma: Redefining resectable hepatocellular carcinoma

Sung Hwan LEE,Sun Young YIM,Sang-Hee KANG,Bo Hwa SOHN,Yun Seong JEONG,Ji-Hyun SHIN,You Rhee CHOI,Jae-Jun SHIM,Jihoon KIM,Henry LI,Sheng GUO,Randy JOHNSON,Ahmed KASEB,Koo Jeong KANG,David WHEELER,Ju-Se 대한외과학회 2019 대한외과학회 학술대회 초록집 Vol.2019 No.10

The LncRNA EPEL Promotes Lung Cancer Cell Proliferation Through E2F Target Activation

Park, Seong-Min,Choi, Eun-Young,Bae, Dong-Hyuck,Sohn, Hyun Ahm,Kim, Seon-Young,Kim, Youn-Jae S. Karger AG 2018 Cellular physiology and biochemistry Vol.45 No.3

<P><B><I>Background/Aims:</I></B> Recent studies have revealed that many long non-coding RNAs (lncRNAs) play oncogenic or tumor-suppressive roles in various cancers. Lung cancer is the leading cause of cancer-related death worldwide, and many lung cancer patients frequently relapse after surgery, even those in the early stages. However, the oncogenic or tumor-suppressive roles and clinical implications of lncRNAs in lung cancer have not been fully elucidated. <B><I>Methods:</I></B> The association between an E2F-mediated cell proliferation enhancing lncRNA (EPEL) expression and lung cancer patient survival was accessed using public microarray data with clinical information. Cancer-related phenotypes were analyzed by the siRNA knockdown of EPEL in two lung cancer cell lines. Gene set analysis of gene expression data were performed to identify pathways regulated by EPEL. RNA immunoprecipitation, RT-qPCR, and ChIP assays were performed to explore the functions of selected target genes regulated by EPEL. <B><I>Results:</I></B> EPEL, known as LOC90768 and MGC45800, was associated with the relapse and survival of lung cancer patients and promoted lung cancer cell proliferation through the activation of E2F target genes. EPEL knockdown specifically down-regulated the expression of cell cycle-related E2F target genes, including Cyclin B1 (CCNB1), in lung cancer cells but not that of apoptosis- or metabolism-related E2F target genes. EPEL interacted with E2F1 and regulated the expression of the E2F target genes by changing the binding efficiency of E2F1 to the E2F target promoters. Moreover, the expression levels of EPEL and CCNB1 both alone and in combination were robust prognostic markers for lung cancer. <B><I>Conclusions:</I></B> Considering its specific effects on cell cycle-related E2F target genes and its significant association with the prognosis of lung cancer patients, we suggest that the transcriptional regulation of EPEL through E2F target genes is potentially a target for the development of novel therapeutic strategies for lung cancer patients.</P>

Epigenetic Activation of Tensin 4 Promotes Gastric Cancer Progression

Mirang Kim,Haejeong Heo,Hee-Jin Kim,Keeok Haam,Hyun Ahm Sohn,Yang-Ji Shin,Hanyong Go,Hyo-Jung Jung,Jong-Hwan Kim,Sang-Il Lee,Kyu-Sang Song,Min-Ju Kim,Haeseung Lee,Eun-Soo Kwon,Seon-Young Kim,Yong Sung 한국분자세포생물학회 2023 Molecules and cells Vol.46 No.5

Gastric cancer (GC) is a complex disease influenced by multiple genetic and epigenetic factors. Chronic inflammation caused by Helicobacter pylori infection and dietary risk factors can result in the accumulation of aberrant DNA methylation in gastric mucosa, which promotes GC development. Tensin 4 (TNS4), a member of the Tensin family of proteins, is localized to focal adhesion sites, which connect the extracellular matrix and cytoskeletal network. We identified upregulation of TNS4 in GC using quantitative reverse transcription PCR with 174 paired samples of GC tumors and adjacent normal tissues. Transcriptional activation of TNS4 occurred even during the early stage of tumor development. TNS4 depletion in GC cell lines that expressed high to moderate levels of TNS4, i.e., SNU-601, KATO III, and MKN74, reduced cell proliferation and migration, whereas ectopic expression of TNS4 in those lines that expressed lower levels of TNS4, i.e., SNU-638, MKN1, and MKN45 increased colony formation and cell migration. The promoter region of TNS4 was hypomethylated in GC cell lines that showed upregulation of TNS4. We also found a significant negative correlation between TNS4 expression and CpG methylation in 250 GC tumors based on The Cancer Genome Atlas (TCGA) data. This study elucidates the epigenetic mechanism of TNS4 activation and functional roles of TNS4 in GC development and progression and suggests a possible approach for future GC treatments.

Regulation of hypoxia responses by flavin adenine dinucleotide‐dependent modulation of HIF ‐1α protein stability

Yang, Suk‐,Jin,Park, Young Soo,Cho, Jung Hee,Moon, Byul,An, Hyun‐,Jung,Lee, Ju Yeon,Xie, Zhi,Wang, Yuli,Pocalyko, David,Lee, Dong Chul,Sohn, Hyun Ahm,Kang, Minho,Kim, Jin Young,Kim, Eunhee EMBO 2017 The EMBO journal Vol.36 No.8

<P>Oxygen deprivation induces a range of cellular adaptive responses that enable to drive cancer progression. Here, we report that lysine-specific demethylase 1 (LSD1) upregulates hypoxia responses by demethylating RACK1 protein, a component of hypoxia-inducible factor (HIF) ubiquitination machinery, and consequently suppressing the oxygen-independent degradation of HIF-1 alpha. This ability of LSD1 is attenuated during prolonged hypoxia, with a decrease in the cellular level of flavin adenine dinucleotide (FAD), a metabolic cofactor of LSD1, causing HIF-1 alpha downregulation in later stages of hypoxia. Exogenously provided FAD restores HIF-1 alpha stability, indicating a rate-limiting role for FAD in LSD1-mediated HIF-1 alpha regulation. Transcriptomic analyses of patient tissues show that the HIF-1 signature is highly correlated with the expression of LSD1 target genes as well as the enzymes of FAD biosynthetic pathway in triple-negative breast cancers, reflecting the significance of FAD-dependent LSD1 activity in cancer progression. Together, our findings provide a new insight into HIF-mediated hypoxia response regulation by coupling the FAD dependence of LSD1 activity to the regulation of HIF-1 alpha stability.</P>