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Clustering of the HCC cases based on CNV (amplifications and deletions). Cases were clustered according to 1324 CNV conditions in the exons or introns of 473 known genes from Partek preprocessing, ignoring areas that do not contain expressed genes. Genes that have CNV changes in <10% (or 9) samples were filtered out. The filtering reduces the data from 93 samples and 473 genes to 78 samples and 15 genes. For details, see Materials and Methods.
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Tissues from 98 human hepatocellular carcinomas (HCCs) obtained from hepatic resections were subjected to somatic copy number variation (CNV) analysis. Most of these HCCs were discovered in livers resected for orthotopic transplantation, although in a few cases, the tumors themselves were the reason for the hepatectomies. Genomic analysis revealed...
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... analysis of 78 cases was based on CNV pres- ent in exons and introns of known expressed genes, ignoring CNV in areas that do not contain expressed genes. Five clear clusters of patients were identified (Fig- ure 4): clusters A to C mainly contain LSP1 deletions, and clusters D1 to D2 contain deletions in five genes on Figure 2. Localization of deletions and amplifications for each chromosome (chr) by moving-window analysis. For genomic visualization of CNV regions cumulated across sample population, we used moving windows of 100 kb and counted the number of cases that contained any CNV region overlapping with the window. ...Citations
... Most studies on GNB1L are related to psychiatric disorders reported, for example, in schizophrenia [77] and autism [78]. Only one report exists in which alterations in copy number variations (CNVs) were found in hepatocellular carcinomas, but only in 18 out of 98 patients [79]; thus, we considered this gene as another prominent candidate for further functional studies in ALL. ...
Acute lymphoblastic leukemia (ALL) in children or adults is characterized by structural and numeric aberrations in chromosomes; these anomalies strongly correlate with prognosis and clinical outcome. Therefore, this work aimed to identify the genes present in chromosomal gain regions found more frequently in patients with acute lymphoblastic leukemia (ALL) and ALL-derived cell lines using comparative genomic hybridization (CGH). In addition, validation of the genes found in these regions was performed utilizing RNAseq from JURKAT, CEM, and SUP-B15 cell lines, as well as expression microarrays derived from a MILE study. Chromosomes with common gain zones that were maintained in six or more samples were 14, 17, and 22, in which a total of 22 genes were identified. From them, NT5C3B, CNP, ACLY, and GNB1L maintained overexpression at the mRNA level in the cell lines and in patients with ALL. It is noteworthy that SALL2 showed very high expression in T-ALL, while JUP was highly expressed in B-ALL lineages. Interestingly, the latter correlated with worse survival in patients. This provided evidence that the measurement of these genes has high potential for clinical utility; however, their expressions should first be evaluated with a sensitive test in a more significant number of patients.
... Infection with HBV or HCV, alcoholic liver disease, and most likely nonalcoholic fatty liver disease are major risk factors for HCC. Hereditary hemochromatosis, alpha1antitrypsin deficiency, autoimmune hepatitis, certain porphyrias, and Wilson's disease are less prevalent causes (5)(6)(7)(8)(9). Gene expression changes, mutations in coding and noncoding regions, and epigenetic changes are among the most common changes (1,(10)(11)(12)(13)(14). ...
MAP/microtubule affinity-regulating kinase 4 (MARK4) is associated with various biological functions, including neuronal migration, cell polarity, microtubule dynamics, apoptosis, and cell cycle regulation, specifically in the G1/S checkpoint, cell signaling, and differentiation. It plays a critical role in different types of cancers. Hepatocellular carcinoma (HCC) is the one of the most common forms of liver cancer caused due to mutations, epigenetic aberrations, and altered gene expression patterns. Here, we have applied an integrated network biology approach to see the potential links of MARK4 in HCC, and subsequently identified potential herbal drugs. This work focuses on the naturally-derived compounds from medicinal plants and their properties, making them targets for potential anti-hepatocellular treatments. We further analyzed the HCC mutated genes from the TCGA database by using cBioPortal and mapped out the MARK4 targets among the mutated list. MARK4 and Mimosin, Quercetin, and Resveratrol could potentially interact with critical cancer-associated proteins. A set of the hepatocellular carcinoma altered genes is directly the part of infection, inflammation, immune systems, and cancer pathways. Finally, we conclude that among all these drugs, Gingerol and Fisetin appear to be the highly promising drugs against MARK4-based targets, followed by Quercetin, Resveratrol, and Apigenin.
... A significant but controversial role for RSU1 in human cancer has been previously reported. Deletion of RSU1 has been demonstrated in hepatocellular carcinoma while increased expression has been shown in breast cancer [7,17,18]. Contradictory results regarding the role of RSU1 in FA signaling, cell adhesion and migration have also been described in different cancer cell lines, while transcripts of RSU1 resulting from alternative splicing with distinct functions seem to account in part for the observed complexity regarding RSU1 cancer-related functions [18][19][20][21]. Since little is known regarding RSU1 in lung adenocarcinoma, we aimed to address its expression, function and prognostic significance in lung adenocarcinoma. ...
... In favor of a tumor suppressor role of RSU1 in cancer and in agreement with our findings, RSU1 has been originally identified by its ability to suppress RAS induced oncogenic growth [4] and overexpression of RSU1 blocked tumor growth in a glioblastoma xenograft mouse model [21,32]. In further agreement with this notion, somatic copy number variation (CNV) analysis in hepatocellular carcinoma showed that the RSU1 gene is frequently deleted in human liver cancer [17] and ectopic expression of RSU1 reduced cell proliferation and growth of breast cancer cells [21,34]. RSU1 was also shown to promote apoptosis in breast cancer cells by inhibiting PINCH1 and activating p53-upregulatedmodulator of apoptosis (PUMA) [34] and repression of RSU1 is implicated in micro RNAs' tumorigenic role in prostate [35] and breast cancer [36]. ...
Ras suppressor-1 (RSU1), originally described as a suppressor of Ras oncogenic transformation, localizes to focal adhesions interacting with the ILK-PINCH-PARVIN (IPP) complex that exerts a well-established oncogenic role in cancer. However, RSU1 implication in lung cancer is currently unknown. Our study aims to address the role of RSU1 in lung adenocarcinoma (LUADC). We here show that RSU1 protein expression by immunohistochemistry is downregulated in LUADC human tissue samples and represents a significant prognostic indicator. In silico analysis of gene chip and RNA seq data validated our findings. Depletion of RSU1 by siRNA in lung cancer cells promotes anchorage-independent cell growth, cell motility and epithelial to mesenchymal transition (EMT). Silencing of RSU1 also alters IPP complex expression in lung cancer cells. The p29 RSU1 truncated isoform is detected in lung cancer cells, and its expression is downregulated upon RSU1 silencing, whereas it is overexpressed upon ILK overexpression. These findings suggest that RSU1 exerts a tumor suppressive role with prognostic significance in LUADC.
... The underlying mechanisms, however, by which CAR affects hepatocellular proliferation are not completely understood. 9 Leukocyte-specific protein-1 (LSP1) is an F-actin binding protein involved in human hepatocellular carcinoma 10,11 as well as bladder and breast cancer. 12e15 In lymphoma cell lines, LSP1 interacts with kinase suppressor of Ras to facilitate the localization of mitogen-activated protein kinase kinase (MEK) and extracellular signal-regulated kinase (ERK) to the cytoskeleton. ...
... In view of the F-actin binding of LSP1 36 and its effects on the cytoskeleton, LSP1 is an important contributor to the mechanosensory effects of regulation of cell proliferation and function. Because LSP1 is involved in breast, 13e15 bladder, 12 and liver 10,21,22,24,26 cancers, understanding how LSP1 functions to suppress hepatocellular proliferation can provide new avenues of investigation to develop novel therapeutics. ajp.amjpathol.org ...
Activation of CAR transcription factor by xenobiotics promotes hepatocellular proliferation, hypertrophy without liver injury, and induces drug metabolism genes. Our previous work demonstrated lymphocyte specific protein-1 (LSP1), an F-actin binding protein and gene involved in human HCC, suppresses hepatocellular proliferation after partial hepatectomy. In this study, we investigated the role of LSP1 in liver enlargement induced by chemical mitogens, a regenerative process independent of tissue loss. We administered TCPOBOP, a direct CAR ligand and strong chemical mitogen, to global Lsp1 knockout (KO) and hepatocyte specific Lsp1 transgenic (TG) mice and measured cell proliferation, hypertrophy, and expression of CAR dependent drug metabolism genes. TG livers displayed a significant decrease in Ki67 labeling and liver to body weight ratios compared to WT on day 2. Surprisingly, this was reversed by day 5, due to hepatocyte hypertrophy. There was no difference in CAR regulated drug metabolism genes between WT and TG. TG livers displayed increased YAP phosphorylation, decreased nuclear YAP and direct interaction between LSP1 and YAP, suggesting LSP1 suppresses TCPOBOP driven hepatocellular proliferation, but not hepatocyte volume, through YAP. Conversely, loss of LSP1 led to increased hepatocellular proliferation on days 2, 5 and 7. LSP1 selectively suppresses CAR induced hepatocellular proliferation, but not drug metabolism, through the interaction of LSP1 with YAP, supporting the role of LSP1 as a selective growth suppressor.
... BAHCC1 is a chromatin transcriptional silencer, implied into cell replication and transcriptional regulation mechanisms. Amplifications and deletions of this gene would make it potentially part of aberrant cell regeneration processes linked to the development of liver cancer, according to still-not-wellknown mechanisms, but possibly due to downstream alterations in the signaling pathways (33). However, there are few data about epigenetic modifications of BAHCC1, although an experimental study by Gitik et al. found an increase in its methylation in the dorsal hippocampus of mice treated with nicotine before adolescence, in an animal model correlating substance abuse in the age of adolescence (or alcohol exposure in utero) with addiction. ...
Pituitary adenomas (PAs), usually benign lesions, can sometimes present with “aggressive” features (rapid growth, local invasiveness, scarce response to conventional treatments). Despite the fact that a few genetic alterations have been associated to this clinical behavior, the role of epigenetic modifications, mainly methylation and miRNAs activity, is now opening new frontiers in this field. We evaluated the methylation profile of 21 PA (11 GH-omas, 10 nonfunctioning tumors—NFPAs) samples from TNS surgery and 5 normal pituitaries, collected at our neurosurgery between 2015 and 2017. DNA was extracted and sequenced, selecting 184,841 target regions. Moreover, methylation profiles were correlated with demographic, radiological, and clinicopathological features. NFPAs showed higher methylation levels vs. GH-omas, with 178 differentially methylated regions (DMRs) mainly consisting of noncoding and intronic sequences, and mostly localized in the open sea regions. We also found three hypermethylated genes ( C7orf50 , GNG7 , and BAHCC1 ) involved in tumorigenesis processes and potentially influencing pituitary tumor pathophysiology. Among the clinicopathological features, only the maximum diameter resulted significantly higher in NFPAs. Our data provide further evidence of the complex epigenetic background of pituitary tumors. In line with the current literature, we confirmed a significant prevalence of hypermethylation in NFPAs vs. GH-omas, whose pathophysiological consequence is yet to be defined.
... It is mainly used to analyze the proteins (>50 kD) encoded by newly recognized large cDNAs (>4 kb), and the genes encoding these proteins are uniformly named by KIAA plus four numbers [4]. To date, few reports have investigated KIAA1217, of which only a few studies have described its relation to the development of cancer [5,[31][32][33][34]. Based on genetic association studies in pancreatic cancer databases, KIAA1217 is upregulated, suggesting that KIAA1217 may be a putative target for pancreatic cancer [32]. ...
... Based on genetic association studies in pancreatic cancer databases, KIAA1217 is upregulated, suggesting that KIAA1217 may be a putative target for pancreatic cancer [32]. Copy number variation of KIAA1217 is also frequently observed in HCC [31] or breast cancer [34]. However, the potential role and mechanism of KIAA1217 in the progression of cancer remains unclear. ...
The survival and prognosis of hepatocellular carcinoma (HCC) are poor, mainly due to metastasis. Therefore, insights into the molecular mechanisms underlying HCC invasion and metastasis are urgently needed to develop a more effective antimetastatic therapy. Here, we report that KIAA1217, a functionally unknown macromolecular protein, plays a crucial role in HCC metastasis. KIAA1217 expression was frequently upregulated in HCC cell lines and tissues, and high KIAA1217 expression was closely associated with shorter survival of patients with HCC. Overexpression and knockdown experiments revealed that KIAA1217 significantly promoted cell migration and invasion by inducing epithelial-mesenchymal transition (EMT) in vitro. Consistently, HCC cells overexpressing KIAA1217 exhibited markedly enhanced lung metastasis in vivo. Mechanistically, KIAA1217 enhanced EMT and accordingly promoted HCC metastasis by interacting with and activating JAK1/2 and STAT3. Interestingly, KIAA1217-activated p-STAT3 was retained in the cytoplasm instead of translocating into the nucleus, where p-STAT3 subsequently activated the Notch and Wnt/β-catenin pathways to facilitate EMT induction and HCC metastasis. Collectively, KIAA1217 may function as an adaptor protein or scaffold protein in the cytoplasm and coordinate multiple pathways to promote EMT-induced HCC metastasis, indicating its potential as a therapeutic target for curbing HCC metastasis.
... In previous studies we showed that alterations of genome and gene expression occurring in HCC are associated with aggressiveness of the cancer. (40,41) However, it was unclear whether these changes contained predictive values for patients with HCC undergoing liver transplants. To explore this possibility, two cohorts based on the surgical timeline were constructed for transcriptome and exome sequencing analyses. ...
Hepatocellular carcinoma (HCC) is one of the most lethal human cancers. Liver transplantation has been an effective approach to treat liver cancer. However, significant numbers of patients with HCC experience cancer recurrence, and the selection of suitable candidates for liver transplant remains a challenge. We developed a model to predict the likelihood of HCC recurrence after liver transplantation based on transcriptome and whole-exome sequencing analyses. We used a training cohort and a subsequent testing cohort based on liver transplantation performed before or after the first half of 2012. We found that the combination of transcriptome and mutation pathway analyses using a random forest machine learning correctly predicted HCC recurrence in 86.8% of the training set. The same algorithm yielded a correct prediction of HCC recurrence of 76.9% in the testing set. When the cohorts were combined, the prediction rate reached 84.4% in the leave-one-out cross-validation analysis. When the transcriptome analysis was combined with Milan criteria using the k -top scoring pairs ( k -TSP) method, the testing cohort prediction rate improved to 80.8%, whereas the training cohort and the combined cohort prediction rates were 79% and 84.4%, respectively. Application of the transcriptome/mutation pathways RF model on eight tumor nodules from 3 patients with HCC yielded 8/8 consistency, suggesting a robust prediction despite the heterogeneity of HCC. Conclusion: The genome prediction model may hold promise as an alternative in selecting patients with HCC for liver transplant.
We have determined algorithms which predict with high accuracy the possibility of a hepatocellular carcinoma (HCC) reappearing to a new transplanted liver, after the original HCC-containing liver resection. The algorithm is based on genomic analyses of the HCC, predicated on transcriptome expression, and gene mutations in selected pathways.
... (44)(45)(46) The analysis of our previous publication showed that Pten loss occurred in 31% (17/55) of HCC samples that were positive for SLC45A2-AMACR. (47) Thus, the combination of Pten loss and gene fusion between SLC45A2 and AMACR may play a critical role in HCC generation. To investigate this hypothesis directly, we cloned SLC45A2-AMACR-FLAG into pT3-E5α to create pT3-SLC45A2-AMACR-FLAG. ...
Chromosome rearrangement is one of the hallmarks of human malignancies. Gene fusion is one of the consequences of chromosome rearrangements. In this report, we show that gene fusion between solute carrier family 45 member 2 (SLC45A2) and alpha‐methylacyl‐coenzyme A racemase (AMACR) occurs in eight different types of human malignancies, with frequencies ranging from 45% to 97%. The chimeric protein is translocated to the lysosomal membrane and activates the extracellular signal‐regulated kinase signaling cascade. The fusion protein promotes cell growth, accelerates migration, resists serum starvation‐induced cell death, and is essential for cancer growth in mouse xenograft cancer models. Introduction of SLC45A2‐AMACR into the mouse liver using a sleeping beauty transposon system and somatic knockout of phosphatase and TENsin homolog (Pten) generated spontaneous liver cancers within a short period. Conclusion: The gene fusion between SLC45A2 and AMACR may be a driving event for human liver cancer development.
... Contrarily, oxidative stress imposed by peroxisome proliferators and subsequent induction of PPARα enables hepatocellular proliferation while inhibiting apoptosis (Reddy et al., 1976;Tachibana et al., 2008). The NOTCH cell fate-regulatory pathway, another probable downstream target of YTHDF1, too, has been shown to be pro-oncogenic, due to its associations with NOTCH coactivator MAML2, a target of genetic alterations, and activation of Sox9-and K19-positive progenitors leading to liver tumorigenesis (Nalesnik et al., 2012;Strazzabosco and Fabris, 2012;Morell and Strazzabosco, 2014). Thus, the relationship between PPAR/NOTCH signaling pathways and the epitranscriptomic role of YTHDF1 is an area that warrants further research. ...
Epidemiological data consistently rank hepatocellular carcinoma (HCC) as one of the leading causes of cancer-related deaths worldwide, often posing severe economic burden on health care. While the molecular etiopathogenesis associated with genetic and epigenetic modifications has been extensively explored, the biological influence of the emerging field of epitranscriptomics and its associated aberrant RNA modifications on tumorigenesis is a largely unexplored territory with immense potential for discovering new therapeutic approaches. In particular, the underlying cellular mechanisms of different hallmarks of hepatocarcinogenesis that are governed by the complex dynamics of m6A RNA methylation demand further investigation. In this review, we reveal the up-to-date knowledge on the mechanistic and functional link between m6A RNA methylation and pathogenesis of HCC.
... The copyright holder for this preprint this version posted February 18, 2021. ; https://doi.org/10.1101/2021.02.18.431696 doi: bioRxiv preprint expression levels of the target gene BAHCC1 were shown to be associated with survival times in different types of cancers such as melanoma [60], liver cancer [61] and pancreatic cancer [62]. ...
Epigenome-wide association studies (EWAS) often detect a large number of differentially methylated sites or regions, many are located in distal regulatory regions. To further prioritize these significant sites, there is a critical need to better understand the functional impact of CpG methylation. Recent studies demonstrated CpG methylation-dependent transcriptional regulation is a widespread phenomenon. Here we present MethReg, an R/Bioconductor package that analyzes matched DNA-methylation and gene-expression data, along with external transcription factor (TF) binding information, to evaluate, prioritize, and annotate CpG sites with high regulatory potential. By simultaneous modeling three key elements that contribute to gene transcription (CpG methylation, target gene expression and TF activity), MethReg identifies TF-target gene associations that are present only in a subset of samples with high (or low) methylation levels at the CpG that influences TF activities, which can be missed in analyses that use all samples. Using real colorectal cancer and Alzheimer's disease datasets, we show MethReg significantly enhances our understanding of the regulatory roles of DNA methylation in complex diseases.
