CHD1L Expression Research Articles

Genome-wide scanning for CHD1L gene in papillary thyroid carcinoma complicated with type 2 diabetes mellitus.

Papillary thyroid carcinoma (PTC) represents the most common subtype of thyroid cancer (TC). This study was set out to explore the potential effect of CHD1L on PTC and type 2 diabetes mellitus (T2DM). We searched for T2DM susceptibility genes through the GWAS database and obtained T2DM-related differentially expressed gene from the GEO database. The expression and clinical data of TC and normal samples were collated from the TCGA database. Receiver operating characteristic (ROC) curve analysis was subsequently applied to assess the sensitivity and specificity of the CHD1L for the diagnosis of PTC. The MCP-counter package in R language was then utilized to generate immune cell score to evaluate the relationship between CHD1L expression and immune cells. Then, we performed functional enrichment analysis of co-expressed genes and DEGs to determine significantly enriched GO terms and KEGG to predict the potential functions of CHD1L in PTC samples and T2DM adipose tissue. From two genes (ABCB9, CHD1L) were identified to be DEGs (p < 1 * 10-5) that exerted effects on survival (HR > 1, p < 0.05) in PTC and served as T2DM susceptibility genes. The gene expression matrix-based scoring of immunocytes suggested that PTC samples with high and low CHD1L expression presented with significant differences in the tumor microenvironment (TME). The enrichment analysis of CHD1L co-expressed genes and DEGs suggested that CHD1L was involved in multiple pathways to regulate the development of PTC. Among them, Kaposi sarcoma-associated herpesvirus infection, salmonella infection and TNF signaling pathways were highlighted as the three most relevant pathways. GSEA analysis, employed to analyze the genome dataset of PTC samples and T2DM adipose tissue presenting with high and low expression groups of CHD1L, suggests that these differential genes are related to chemokine signaling pathway, leukocyte transendothelial migration and TCELL receptor signaling pathway. CHD1L may potentially serve as an early diagnostic biomarker for PTC, and a target of immunotherapy for PTC and T2DM.

Suppressing CHD1L reduces the proliferation and chemoresistance in osteosarcoma

Osteosarcoma (OS) is the most common bone malignant tumor. However, the genetic basis of OS pathogenesis is still not understood, and occurrence of chemo-resistance is a major reason for the high morbidity of OS patients. Recently, chromodomain helicase/ATPase DNA binding protein 1-like gene (CHD1L) has been identified as a gene related to malignant tumor progression. Unfortunately, its effects on OS development and drug resistance are still not understood. In the study, we attempted to investigate the effects of CHD1L on tumorigenesis and chemoresistance in OS. We found that CHD1L expression was markedly up-regulated in OS samples, especially in cisplatin (cDDP)-resistant patients. We also showed that OS cells with CHD1L knockdown were more sensitive to cDDP treatment with lower IC50 values. In addition, we found that CHD1L deletion markedly reduced cell proliferation and induced apoptosis in OS cells with cDDP resistance. Moreover, the properties of cancer stem cells were highly suppressed in cDDP-resistant OS cells following CHD1L knockdown. Furthermore, multidrug resistance protein 1 (MDR-1) expression levels were dramatically decreased in OS cells with cDDP resistance when CHD1L was suppressed. Functional analysis indicated that CHD1L knockdown clearly restrained the activation of ERK1/2, protein kinase B (AKT) and NF-κB signaling pathways in cDDP-resistant OS cells. Consistently, animal experiments suggested that CHD1L suppression mitigated cDDP resistance in the generated in vivo xenografts. Collectively, CHD1L could modulate chemoresistance of OS cells to cDDP, and thus may be inspiring findings for overcoming drug resistance in OS.

Effect of chromodomain helicase/ATPase DNA binding protein 1-like gene on the invasion and metastasis of tongue squamous cell carcinoma CAL27 cells.

A study was conducted to investigate the molecular mechanism of chromodomain helicase/ATPase DNA binding protein 1-like gene (CHD1L) influencing the invasion and metastasis of tongue squamous cell carcinoma and to provide a new target for clinical inhibition of invasion and metastasis of tongue squamous cell carcinoma. Ualcan website was used to analyze the expression of CHD1L in normal epithelial tissue and primary head and neck squamous cell carcinoma and to analyze the effect of lymph node metastasis on the expression of CHD1L in tissues with head and neck squamous cell carcinoma. The relationship between CHD1L expression and the survival rate of patients with head and neck squamous cell carcinoma was tested by the GEPIA website. Western blot was used to quantify the levels of CHD1L protein in human tongue squamous cell carcinoma CAL27 and immortalized human skin keratinocyte cell HaCaT. After knocking down CAL27 in human tongue squamous cell carcinoma cells with an RNA interference plasmid, the cells were designated as SiCHD1L/CAL27 and Scr/CAL27. Western blot was utilized to detect the expression of CHD1L in each group of cells. The change in CAL27 cell proliferation ability was tested by EdU proliferation test after CHD1L knockdown. The change of cell migration ability of each group cells was tested through the wound healing assay. Western blot was used to detect epithelial-mesenchymal transition (EMT) marker E-cadherin and Vimentin protein expression levels. Ualcan database showed that the expression of CHD1L in primary head and neck squamous cell carcinoma tissues was higher than in normal epithelial tissues and in head and neck squamous cell carcinoma tissues with lymph node metastasis. GEPIA website analysis showed that the overall survival rate of patients with head and neck squamous cell carcinoma with high expression of CHD1L was significantly lower than that of patients with low expression. Western blot results showed that CHD1L expression in human tongue squamous carcinoma cells CAL27 was higher than that of human normal skin cells HaCaT. CHD1L expression in SiCHD1L/CAL27 cells was much lower than that in Scr/CAL27 cells. Results of EdU proliferation experiments showed the significant reduction in the cell proliferation ability of the SiCHD1L/CAL27 cells. Results of the wound healing experiments showed the reduction in the migration capacity of the SiCHD1L/CAL27 cells. The expression of E-cadherin increased, whereas that of Vimentin decreased, in SiCHD1L/CAL27 cells. CHD1L promoted the EMT, proliferation, migration, and invasion ability of tongue squamous cell carcinoma cells.

First-in-Class Inhibitors of Oncogenic CHD1L with Preclinical Activity against Colorectal Cancer.

Since the discovery of CHD1L in 2008, it has emerged as an oncogene implicated in the pathology and poor prognosis of a variety of cancers, including gastrointestinal cancers. However, a mechanistic understanding of CHD1L as a driver of colorectal cancer has been limited. Until now, there have been no reported inhibitors of CHD1L, also limiting its development as a molecular target. We sought to characterize the clinicopathologic link between CHD1L and colorectal cancer, determine the mechanism(s) by which CHD1L drives malignant colorectal cancer, and discover the first inhibitors with potential for novel treatments for colorectal cancer. The clinicopathologic characteristics associated with CHD1L expression were evaluated using microarray data from 585 patients with colorectal cancer. Further analysis of microarray data indicated that CHD1L may function through the Wnt/TCF pathway. Thus, we conducted knockdown and overexpression studies with CHD1L to determine its role in Wnt/TCF-driven epithelial-to-mesenchymal transition (EMT). We performed high-throughput screening (HTS) to identify the first CHD1L inhibitors. The mechanism of action, antitumor efficacy, and drug-like properties of lead CHD1L inhibitors were determined using biochemical assays, cell models, tumor organoids, patient-derived tumor organoids, and in vivo pharmacokinetics and pharmacodynamics. Lead CHD1L inhibitors display potent in vitro antitumor activity by reversing TCF-driven EMT. The best lead CHD1L inhibitor possesses drug-like properties in pharmacokinetic/pharmacodynamic mouse models. This work validates CHD1L as a druggable target and establishes a novel therapeutic strategy for the treatment of colorectal cancer.

Corrigendum] CHD1L is associated with poor survival and promotes the proliferation and metastasis of intrahepatic cholangiocarcinoma.

Subsequent to the publication of the above paper, the authors have realized that the second affiliation for the second named author, YiChai, was not included with the affiliations. His second affiliation should have been listed as: "Department of Neurosurgery, Yuquan Hospital, School of Clinical Medicine, Tsinghua University, Beijing100040, China." Therefore, the author affiliations for this paper should have appeared as follows: SHIMIAO LI1*, YI CHAI2,3*, YANBAO DING4, TINGHAO YUAN4, CHANGWEN WU5 and CHANGWEN HUANG1. 1Department of Hepatobiliary Surgery, Jiangxi Provincial People's Hospital, Nanchang, Jiangxi330006; 2Department of Neurosurgery, Yuquan Hospital, School of Clinical Medicine, Tsinghua University, Beijing100040; 3Department of Neurosurgery, Shangrao People's Hospital, Shangrao, Jiangxi334000; 4Department of Hepatobiliary Surgery; 5Department of Urology Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi330006, P.R.China. The authors regret that this was not corrected prior to the publication of the paper, and apologize to the readers for any inconvenience caused. [the original article was published in Oncology Reports 42: 657‑669, 2019; DOI: 10.3892/or.2019.7174].

CHD1L is associated with poor survival and promotes the proliferation and metastasis of intrahepatic cholangiocarcinoma.

Chromodomain helicase/ATPase DNA-binding protein 1-like gene (CHD1L) is a new oncogene which has been confirmed to be crucial to the progression of many solid tumors. In the present study, the expression of CHD1L was found to be upregulated in intrahepatic cholangiocarcinoma (ICC), which was significantly associated with histological differentiation (P=0.011), vascular invasion (P=0.002), lymph node metastasis (P=0.008) and TNM stage (P=0.001). Kaplan-Meier survival analysis revealed that ICC patients with positive CHD1L expression had shorter overall and disease-free survival than those with negative CHD1L expression. Functional study found that CHD1L exhibited strong oncogenic roles, including increased cell growth by CCK-8 assay, colony formation by plate colony formation assay, G1/S transition by flow cytometry and tumor formation in nude mice. In addition, RNAi-mediated silencing of CHD1L inhibited ICC invasion and metastasis by wound healing, Transwell migration and Matrigel invasion assays in vitro and in vivo. Collectively, our results show that CHD1L is upregulated and promotes the proliferation and metastasis of ICC cells. CHD1L acts as an oncogene and may be a prognostic factor or therapeutic target for patients with ICC.

CHD1L contributes to cisplatin resistance by upregulating the ABCB1\u2013NF-\u03baB axis in human non-small-cell lung cancer

Chromodomain helicase/ATPase DNA binding protein 1-like gene (CHD1L) is a recently identified gene associated with malignant tumor progression and patient chemotherapy resistance in human hepatocellular carcinoma (HCC). Previously, we found an association between CHD1L overexpression and poor patient survival in non-small-cell lung cancer (NSCLC). However, little is known about the relationship between CHD1L expression and chemotherapy resistance of NSCLC. By employing immunohistochemistry, we analyzed the expression of CHD1L in NSCLC samples and elucidated the roles and mechanism of CHD1L in NSCLC chemoresistance. We found that the increased expression of CHD1L is positively correlated with a shorter survival time of patients who had received chemotherapy after surgery. We also found that the expression of CHD1L was increased after cisplatin treatment in A549 cells. Conversely, the depletion of CHD1L in cisplatin-resistance cells increased the cell sensitivity to cisplatin, indicating that CHD1L plays a critical role in cisplatin resistance of NSCLC cells. Importantly, we identified the ATP-Binding Cassette Sub-Family B Member (ABCB1) gene as a potential downstream target of CHD1L in NSCLC cells. Knocking down ABCB1 coupled with ectopic expression of CHD1L enhanced the effect of cisplatin on NSCLC cells apoptosis. In addition, overexpressed CHD1L increase the transcription of c-Jun which targeted directly to the promoter of ABCB1. Our data demonstrate that CHD1L could induce cisplatin resistance in NSCLC via c-Jun-ABCB1–NF-κB axis, and may serve as a novel predictive marker and the potential therapeutic target for cisplatin resistance in NSCLC.

CHD1L Promotes Neuronal Differentiation in Human Embryonic Stem Cells by Upregulating PAX6.

Chromodomain helicase DNA-binding protein 1-like gene (CHD1L) was initially isolated as a candidate oncogene in hepatocellular carcinoma, and it has been associated with many malignancies. Knockdown of Chd1l in zygote-stage mouse embryos resulted in developmental arrest, suggesting that Chd1l is required for mouse early development. However, the exact role of CHD1L in development, especially in humans, has not been reported. In this study, we found that overexpression of CHD1L in human embryonic cells (hESCs) upregulated the expression of ectoderm genes, especially PAX6. Furthermore, ectopic expression of CHD1L promoted hESCs to differentiate into neuroepithelium both in embryoid bodies and in directed neuronal differentiation. Knockdown of CHD1L significantly impaired neuroepithelial differentiation of hESCs. Interestingly, Chd1l colocalized with a PAX6-positive cell population and was highly expressed in the ventricular (germinal) zone of fetal mice. Taken together, these data suggest that CHD1L promotes neuronal differentiation of hESCs and may play an important role in nervous system development.

CHD1L Expression Increases Tumor Progression and Acts as a Predictive Biomarker for Poor Prognosis in Pancreatic Cancer.

The chromodomain helicase/ATPase DNA binding protein 1-like gene (CHD1L) plays a key role in controlling various cellular phenomena, including immune-mediated inflammation, transformation, apoptosis, cell cycle progression, and proliferation. This study investigated the function and clinical significance of CHD1L protein expression in pancreatic cancer (PC). We analyzed CHD1L expression in surgical specimens from 112 PC patients. The correlation between the clinical characteristics and prognosis was also determined. Futhermore, cell proliferation were measured using EDU, and a molecular mechanism of Wnt/β-catenin pathway regulation by CHD1L was explored. CHD1L protein expression was significantly higher in PC patients with regard to the tumor grade, stage, size, differentiation and lymph node status. Increased CHD1L protein expression was significantly associated with poor overall survival. Multivariate analyses revealed that high CHD1L expression was an independent predictive marker for the recurrence and poor prognosis of pancreatic cancer. Furthermore, silencing of CHD1L expression by RNAi effectively abolished the proliferative abilities of CHD1L in vivo and in vitro. We found that the Wnt/β-catenin pathway contributed to the effect of CHD1L-mediated pancreatic cancer proliferation. Taken together, our data provide a novel evidence for the biological and clinical significance of CHD1L as a potential biomarker, and we demonstrate that CHD1L-Wnt/β-catenin might be a novel pathway involved in pancreatic cancer progression.

Cell adhesion induces overexpression of chromodomain helicase/ATPase DNA binding protein 1-like gene (CHD1L) and contributes to cell adhesion-mediated drug resistance (CAM-DR) in multiple myeloma cells

Previous studies have shown that chromodomain helicase/ATPase DNA binding protein 1-like gene (CHD1L) exerts its anti-apoptotic function in many solid cancers. However, its role in human multiple myeloma (MM) has not been thoroughly elucidated. In this study, we investigate the role of CHD1L in MM. Preliminarily, up-regulation and down-regulation assay verified that CHD1L exerts its anti-apoptotic role through the apoptotic pathway involving caspase-9–caspase-3 apoptotic pathway in MM cells. In addition, we determined that CHD1L expression is increased when MM cells were adhered to fibronectin (FN) or bone marrow stromal cell line HS-5 cells and cell adhesion assay indicated that CHD1L siRNA reversed the high cell adhesion rate. Consistent with the reduced adhesion rate, the cells translated to a compromised cell adhesion-mediated drug resistance (CAM-DR) phenotype in MM. In summary, we will propose strategies for developing a CHD1L inhibitor for potential treatment of MM.

Chromodomain Helicase/ATPase DNA-Binding Protein 1-Like Gene (CHD1L) Expression and Implications for Invasion and Metastasis of Breast Cancer.

BackgroundChromodomain helicase/ATPase DNA-binding protein 1-like gene (CHD1L), also known as ALC1 (amplified in liver cancer 1 gene), is a new oncogene amplified in many solid tumors. Whether this gene plays a role in invasion and metastasis of breast cancer is unknown.MethodsImmunohistochemistry was performed to detect the expression of CHD1L in patients with invasive ductal carcinoma and normal mammary glands. Chemotaxis, wound healing, and Transwell invasion assays were also performed to examine cell migration and invasion. Western blot analysis was conducted to detect the expression of CHD1L, MMP-2, MMP-9, pAkt/Akt, pARK5/ARK5, and pmTOR/mTOR. Moreover, ELISA was carried out to detect the expression levels of MMP-2 and MMP-9. Nude mice xenograft model was used to detect the invasion and metastasis of breast cancer cell lines.ResultsCHD1L overexpression was observed in 112 of 268 patients (41.8%). This overexpression was associated with lymph node metastasis (P = 0.008), tumor differentiation (P = 0.020), distant metastasis (P = 0.026), MMP-2 (P = 0.035), and MMP-9 expression (P = 0.022). In the cell experiment, reduction of CHD1L inhibited the invasion and metastasis of breast cancer cells by mediating MMP-2 and MMP-9 expression. CHD1L knockdown via siRNA suppressed EGF-induced pAkt, pARK5, and pmTOR. This knockdown inhibited the metastasis of breast cancer cells into the lungs of SCID mice.ConclusionsCHD1L promoted the invasion and metastasis of breast cancer cells via the PI3K/Akt/ARK5/mTOR/MMP signaling pathway. This study identified CHD1L as a potential anti-metastasis target for therapeutic intervention in breast cancer.

Overexpression of N-terminal kinase like gene promotes tumorigenicity of hepatocellular carcinoma by regulating cell cycle progression and cell motility.

Amplification and overexpression of CHD1L is one of the most frequent genetic alterations in hepatocellular carcinoma (HCC). Here we found that one of CHD1L downstream targets, NTKL, was frequently upregulated in HCC, which was significantly correlated with vascular invasion (P = 0.012) and poor prognosis (P = 0.050) of HCC. ChIP assay demonstrated the binding of CHD1L to the promoter region of NTKL. QRT-PCR study showed that the expression of NTKL positively correlated with CHD1L expression in both clinical samples and cell lines. Functional study found that NTKL had strong oncogenic roles, including increased cell growth, colony formation in soft agar, and tumor formation in nude mice. Further study found that NTKL could promote G1/S transition by decreasing P53 and increasing CyclinD1 expressions. NTKL overexpression could accelerate the mitotic exit and chromosome segregation, which led to the cytokinesis failure and subsequently induced apoptosis. NTKL also regulated cell motility by facilitating philopodia and lamellipodia formation through regulating F-actin reorganization and the phosphorylation of small GTPase Rac1/cdc42. Using co-IP and mass spectrometry approach, we identified the large GTPase dynamin2 as an interacting protein of NTKL, which might be responsible for the phenotype alterations caused by NTKL overexpression, such as cytokinesis failure, increased cell motility and abnormal of cell division.

Presence of CHD1L over-expression is associated with aggressive tumor biology and is a novel prognostic biomarker for patient survival in human breast cancer.

BackgroundThe chromodomain helicase/adenosine triphosphatase DNA binding protein 1–like gene (CHD1L) is a recently identified oncogene localized at 1q21. CHD1L protein over-expression in primary hepatocellular carcinoma is correlated with enhanced apoptosis inhibition, reduced chemosensitivity and shortened patient survival. However, CHD1L protein status or mRNA expression in breast cancer and its clinical significance remain obscure.Material and MethodsIn this study, immunohistochemical staining for CHD1L expression was performed on tissue microarrays containing 179 primary invasive breast cancers and 65 matched normal breast tissue specimens. Clinico-pathological features were collected and compared between different CHD1L statuses. Kaplan-Meier curves were applied to estimate disease-free survival (DFS) and overall survival (OS). Cox regression was used to identify independent prognostic factors. Also, quantitative real-time polymerase chain reaction (QRT-PCR) was employed to evaluate the mRNA level expression of CHD1L in six breast cancer cell lines.ResultsPresence of CHD1L over-expression was observed in 87 of the 179 patients (48.6%), which associated with a younger age (P = 0.011), higher grade (P = 0.004), higher Ki-67 index (P = 0.018) and HER2 over-expression/amplification (P = 0.037). After a median follow-up of 55 months, patients with presence of CHD1L over-expression had significantly poorer DFS (82.6% Vs 76.3%, P = 0.035), but not OS (87.0% Vs 94.9%, P = 0.439). In multivariate analysis, CHD1L status (HR = 2.169, [95%CI, 1.029–4.573], P = 0.042), triple negative subtype (HR = 2.809, [95%CI 1.086–7.264], P = 0.033) and HER2 positive subtype (HR = 5.221, [95%CI 1.788–15.240], P = 0.002) were identified as independent prognostic factors for DFS. In vitro study indicated that relative mRNA expression level of CHD1L was higher in breast cancer cell lines, especially in MDA-MB-231 and LM2-4175, when compared to normal breast epithelial cell line.ConclusionsPresence of CHD1L over-expression is probably associated with aggressive tumor biology in breast cancer. CHD1L status might be a novel prognostic biomarker for patients with breast cancer.

Expression of CHD1L in colorectal cancer and its effect on colorectal cancer cell proliferation

Expression of CHD1L in colorectal cancer and its effect on colorectal cancer cell proliferation

CHD1L is a novel independent prognostic factor for gastric cancer

Chromodomain helicase/ATPase DNA binding protein 1-like gene (CHD1L) is involved in malignancies. However, the role of CHD1L in gastric cancer (GC) has not been elucidated. The aim of this study is to explore the clinical role of CHD1L in GC. The gene and protein expression levels of CHD1L were detected by quantitative real-time PCR and Western blot analysis in fresh samples of GC and paired adjacent noncancerous tissue (n=34). We evaluated the CHD1L expression by immunohistochemistry in a large number of GC patients (n=616) and paired adjacent noncancerous tissues from December 1, 2004 to December 1, 2008. The correlations of CHD1L expression with clinicopathological features and clinical outcome were analyzed. The gene and protein expression levels of CHD1L were higher in fresh samples of GC than in paired adjacent noncancerous tissues as determined by quantitative real-time PCR and Western blot analysis. Immunohistochemical analysis showed that positive expression rates of CHD1L in GC and paired adjacent noncancerous tissues were 58.7% (361/616) and 7.3% (45/616), respectively. CHD1L positivity was significantly associated with clinical stage and distant metastasis. GC patients with positive CHD1L expression had shorter overall survival than those with negative CHD1L expression. Multivariate analysis showed that CHD1L was an independent prognostic marker for overall survival [Hazard Ratio (HR)=5.952, 95% confidence interval (CI)=3.194-11.187, P=0.0043]. These results indicated that CHD1L could serve as a prognostic marker for GC.

CHD1L: a new candidate gene for congenital anomalies of the kidneys and urinary tract (CAKUT)

Recently, we identified a microduplication in chromosomal band 1q21.1 encompassing the CHD1L/ALC1 gene encoding a chromatin-remodelling enzyme in congenital anomalies of the kidneys and urinary tract (CAKUT) patient. To explore the role of CHD1L in CAKUT, we screened 85 CAKUT patients for mutations in the CHD1L gene and performed functional analyses of the three heterozygous missense variants detected. In addition, we quantitatively determined CHD1L expression in multiple human fetal and adult tissues and analysed expression of CHD1L protein in human embryonal, adult and hydronephrotic kidney sections. Two of three novel heterozygous missense variants identified in three patients were not found in >400 control chromosomes. All variants lead to amino acid substitutions in or near the CHD1L macro domain, a poly-ADP-ribose (PAR)-binding module interacting with PAR polymerase 1 (PARP1), and showed decreased interaction with PARP1 by pull-down assay of transfected cell lysates. Quantitative messenger RNA analysis demonstrated high CHD1L expression in human fetal kidneys, and levels were four times higher than in adult kidneys. In the human embryo at 7-11 weeks gestation, CHD1L immunolocalized in the early ureteric bud and the S- and comma-shaped bodies, critical stages of kidney development. In normal postnatal sections, CHD1L was expressed in the cytoplasm of tubular cells in all tubule segments. CHD1L expression appeared higher in the hydronephrotic kidney of one patient with a hypofunctional CHD1L variant than in normal kidneys, recapitulating high fetal levels. Our data suggest that CHD1L plays a role in kidney development and may be a new candidate gene for CAKUT.

CHD1L promotes hepatocellular carcinoma progression and metastasis in mice and is associated with these processes in human patients

Chromodomain helicase/ATPase DNA binding protein 1-like gene (CHD1L) is a recently identified oncogene localized at 1q21, a frequently amplified region in hepatocellular carcinoma (HCC). To explore its oncogenic mechanisms, we set out to identify CHD1L-regulated genes using a chromatin immunoprecipitation-based (ChIP-based) cloning strategy in a human HCC cell line. We then further characterized 1 identified gene, ARHGEF9, which encodes a specific guanine nucleotide exchange factor (GEF) for the Rho small GTPase Cdc42. Overexpression of ARHGEF9 was detected in approximately half the human HCC samples analyzed and positively correlated with CHD1L overexpression. In vitro and in vivo functional studies in mice showed that CHD1L contributed to tumor cell migration, invasion, and metastasis by increasing cell motility and inducing filopodia formation and epithelial-mesenchymal transition (EMT) via ARHGEF9-mediated Cdc42 activation. Silencing ARHGEF9 expression by RNAi effectively abolished the invasive and metastatic abilities of CHD1L in mice. Furthermore, investigation of clinical HCC specimens showed that CHD1L and ARHGEF9 were markedly overexpressed in metastatic HCC tissue compared with healthy tissue. Increased expression of CHD1L was often observed at the invasive front of HCC tumors and correlated with venous infiltration, microsatellite tumor nodule formation, and poor disease-free survival. These findings suggest that CHD1L-ARHGEF9-Cdc42-EMT might be a novel pathway involved in HCC progression and metastasis.

Transgenic CHD1L Expression in Mouse Induces Spontaneous Tumors

BackgroundAmplification of 1q21 is the most frequent genetic alteration in hepatocellular carcinoma (HCC), which was detected in 58–78% of primary HCC cases by comparative genomic hybridization (CGH). Using chromosome microdissection/hybrid selection approach we recently isolated a candidate oncogene CHD1L from 1q21 region. Our previous study has demonstrated that CHD1L had strong oncogenic ability, which could be effectively suppressed by siRNA against CHD1L. The molecular mechanism of CHD1L in tumorigenesis has been associated with its role in promoting cell proliferation.Methodology/Principal FindingsTo further investigate the in vivo oncogenic role of CHD1L, CHD1L ubiquitous-expression transgenic mouse model was generated. Spontaneous tumor formations were found in 10/41 (24.4%) transgenic mice, including 4 HCCs, but not in their 39 wild-type littermates. In addition, alcohol intoxication was used to induce hepatocyte pathological lesions and results found that overexpression of CHD1L in hepatocytes could promote tumor susceptibility in CHD1L-transgenic mice. To address the mechanism of CHD1L in promoting cell proliferation, DNA content between CHD1L-transgenic and wildtype mouse embryo fibroblasts (MEFs) was compared by flow cytometry. Flow cytometry results found that CHD1L could facilitate DNA synthesis and G1/S transition through the up-regulation of Cyclin A, Cyclin D1, Cyclin E, CDK2, and CDK4, and down-regulation of Rb, p27Kip1, and p53.Conclusion/SignificanceTaken together, our data strongly support that CHD1L is a novel oncogene and plays an important role in HCC pathogenesis