A study on genotypes and phenotypes of short stature caused by epigenetic modification gene variants.

Mendelian disorders of the epigenetic machinery (MDEMs) are caused by genetic mutations, a considerable fraction of which are associated with epigenetic modification. These MDEMs exhibit phenotypic overlap broadly characterized by multiorgan abnormalities. The variant detected in genes associated with epigenetic modification can lead to short stature accompanied with multiple system abnormalities. This study is aimed at presenting and summarizing the diagnostic rate, clinical, and genetic profile of MDEMs-associated short stature. Two hundred and fourteen short-stature patients with multiorgan abnormalities were enrolled. Clinical information and whole exome sequence (WES) were analyzed for these patients. WES identified 33 pathogenic/likely pathogenic variants in 19 epigenetic modulation genes (KMT2A, KMT2D, KDM6A, SETD5, KDM5C, HUWE1, UBE2A, NIPBL, SMC1A, RAD21, CREBBP, CUL4B, BPTF, ANKRD11, CHD7, SRCAP, CTCF, MECP2, UBE3A) in 33 patients (15.4%). Of note, 19 variants had never been reported previously. Furthermore, these 33 variants were associated with 16 different disorders with overlapping clinical features characterized by development delay/intelligence disability (31/33; 93.9%), small hands (14/33; 42.4%), clinodactyly of the 5th finger (14/33; 42.4%), long eyelashes (13/33; 39.4%), and hearing impairment (9/33; 27.3%). Additionally, several associated phenotypes are reported for the first time: clubbing with KMT2A variant, webbed neck with SETD5 variant, retinal detachment with CREBBP variant, sparse lateral eyebrow with HUWE1 variant, and long palpebral fissure with eversion of the lateral third of the low eyelid with SRCAP variant.Conclusions: Our study provided a new conceptual framework for further understanding short stature. Specific clinical findings may indicate that a short-stature patient may have an epigenetic modified gene variant.

Knockdown of Kmt2d leads to growth impairment by activating the Akt/ß-catenin signaling pathway.

The KMT2D variant-caused Kabuki syndrome (KS) is characterized by short stature as a prominent clinical characteristic. The initiation and progression of body growth are fundamentally influenced by chondrocyte proliferation. Uncertainty persists regarding the possibility that KMT2D deficiency affects growth by impairing chondrocyte proliferation. In this study, we used the CRISPR/Cas13d technique to knockdown kmt2d in zebrafish embryos and lentivirus to create a stable Kmt2d gene knockdown cell line in chondrocytes (ATDC5 cells). We also used CCK8 and flow cytometric studies, respectively, to determine proliferation and cell cycle state. The relative concentrations of phosphorylated Akt (ser473), phosphorylated ß-catenin (ser552), and cyclin D1 proteins in chondrocytes and zebrafish embryos were determined by using western blots. In addition, Akt inhibition was used to rescue the phenotypes caused by kmt2d deficiency in chondrocytes, as well as a zebrafish model that was generated. The results showed that a knockdown of kmt2d significantly decreased body length and resulted in aberrant cartilage development in zebrafish embryos. Furthermore, the knockdown of Kmt2d in ATDC5 cells markedly increased proliferation and accelerated the G1/S transition. In addition, the knockdown of Kmt2d resulted in the activation of the Akt/ß-catenin signaling pathway in ATDC5 cells. Finally, Akt inhibition could partly rescue body length and chondrocyte development in the zebrafish model. Our study demonstrated that KMT2D modulates bone growth conceivably via regulation of the Akt/ß-catenin pathway.

A case of left atrial intimal sarcoma with rhabdomyosarcoma differentiation: a case report and literature review.

Primary cardiac malignancies are rare, with cardiac sarcomas being the main type. Among these, intimal sarcomas are the most common. However, they tend to occur in the great vessels and are rare in the heart, with only a few isolated cases reported. We report a challenging case of a patient with left atrial intimal sarcoma with rhabdomyosarcoma differentiation. The patient was admitted after a physical examination detected left heart occupancy, and initial imaging suspected a left atrial thrombus. The patient then underwent extracorporeal circulation-assisted open cardiac surgery with resection of an atrial mass. The postoperative pathological findings were suggestive of an arterial intimal sarcoma, which included areas of rhabdomyosarcoma differentiation within the tumor tissue. Unfortunately, the patient's tumor recurred 4 months later, and she died due to treatment failure. This case highlights the rarity and risk of misdiagnosis of cardiac intimal sarcoma. Additionally, we aim to improve the understanding of intimal sarcoma through a review of immunohistochemistry and gene amplification techniques.

Metastasis of ovarian dysgerminoma in a postmenopausal patient: a rare case report.

Ovary dysgerminoma is one of the most good prognosis malignant tumor, which has a 5-year overall survival rate exceeding to 90%. Generally, the incidence of ovarian dysgerminoma (OD) is relatively low, accounting for ~0.6% of all ovarian tumors. Usually, it mainly occurs in very young women, about 85% of patients under 30 years old and is rare in middle-aged especially in elderly ones. This ovary dysgerminoma case report presents a 58-year-old menopausal postmenopausal woman which has a poor prognosis. Therefore, there may be differences between the elderly and young women in clinical characteristic that require separate management. This case reports a postmenopausal woman who was diagnosed with ovary dysgerminoma. After surgery, the patient was treated chemotherapy with bleomycin, etoposide, and cisplatin (BEP) according to the treatment guidelines. Unusually, the patient developed bone marrow suppression and lymph node metastasis in final. This report explored the clinical characteristic in postmenopausal woman dysgerminoma. Changes in lactate dehydrogenase (LDH) throughout the course of the disease are closely related to the progression. The patient had a disease progression when treated with the conventional treatment (BEP). The applicability of this treatment protocol to postmenopausal patients requires further research. Postmenopausal woman dysgerminoma is rare but rapid progress. Whether BEP is suitable for OD in middle-aged and elderly people remains to be further validated in the future. LDH may be a potential biomarker for monitoring the progression of OD in the elderly.

Value of faecal exfoliated cells in colorectal tumour screening using SDC2 methylation test.

BACKGROUND: This study aimed to evaluate the diagnostic value of a non-invasive methylation gene test in clinical colorectal tumour screening. METHOD: The quantitative methylation-specific PCR technique was used to detect faecal methylated syndecan-2 (mSDC2) in patients who received the screening of colorectal cancer (CRC).To evaluate the positive predictive value (PPV) of mSDC2 in patients with colorectal cancer, advanced adenoma (AA), and colorectal tumor (CRN) in risk factor stratification. RESULTS: The PPV of CRC, CRC + AA and CRN in male patients were 28.03%, 43.55% and 56.24%, respectively, which were higher than female patients. The positive detection rate of mSDC2 and the PPV of CRC gradually increased with age; The PPV in patients aged over 80 years was up to 78.05%, which was more significant than in younger patients with CRC. The PPV of CRC, AA and CRN were 37.10%, 11.80% and 63.37%, respectively. mSDC2 has a high detection rate of 85-100% in AA with intramucosal carcinoma alone or in combination with severe atypical hyperplasia or villous adenoma. CONCLUSION: The mSDC2 test has a higher PPV in patients with colorectal cancer and colorectal adenoma (AD), especially in high-risk groups over 50 years of age, and may help in the early diagnosis of colorectal tumours in the future.

A versatile toolkit for overcoming AAV immunity.

Recombinant adeno-associated virus (AAV) is a promising delivery vehicle for in vivo gene therapy and has been widely used in >200 clinical trials globally. There are already several approved gene therapy products, e.g., Luxturna and Zolgensma, highlighting the remarkable potential of AAV delivery. In the past, AAV has been seen as a relatively non-immunogenic vector associated with low risk of toxicity. However, an increasing number of recent studies indicate that immune responses against AAV and transgene products could be the bottleneck of AAV gene therapy. In clinical studies, pre-existing antibodies against AAV capsids exclude many patients from receiving the treatment as there is high prevalence of antibodies among humans. Moreover, immune response could lead to loss of efficacy over time and severe toxicity, manifested as liver enzyme elevations, kidney injury, and thrombocytopenia, resulting in deaths of non-human primates and patients. Therefore, extensive efforts have been attempted to address these issues, including capsid engineering, plasmapheresis, IgG proteases, CpG depletion, empty capsid decoy, exosome encapsulation, capsid variant switch, induction of regulatory T cells, and immunosuppressants. This review will discuss these methods in detail and highlight important milestones along the way.

miR-138-5p Inhibits Vascular Mimicry by Targeting the HIF-1α/VEGFA Pathway in Hepatocellular Carcinoma.

Tumour vascular mimicry (VM) is the process by which new blood vessels are formed by tumour cells rather than endothelial cells. An increasing number of studies have revealed that the VM process is associated with cancer progression and metastasis. MiR-138-5p has been reported to act as a tumour suppressor in many cancers. However, the role and underlying mechanism of miR-138-5p in hepatocellular carcinoma (HCC) VM remain unclear. In this study, VM density was detected by CD31/periodic acid-Schiff double staining in HCC clinical specimens. We found that miR-138-5p expression correlated strongly and negatively with microvessel density. Additionally, the miR-138-5p mimic or inhibitor decreased or increased, respectively, tube formation capacity in HepG2 and Hep3B cells. Consistent with this finding, miR-138-5p repressed vessel density in vivo. Moreover, miR-138-5p targeted hypoxia-inducible factor 1α (HIF-1α) and regulated the expression of HIF-1α and vascular endothelial growth factor A (VEGFA), which are established classical master regulators for angiogenesis. Consistent with these findings, the HIF-1α inhibitor CAY10585 effectively blocked HCC cell VM and VEGFA expression. In conclusion, miR-138-5p inhibits HepG2 and Hep3B cell VM by blocking the HIF-1α/VEGFA pathway. Therefore, miR-138-5p may serve as a useful therapeutic target for miRNA-based HCC therapy.

Identification of a 5-Hydroxymethylation Signature in Circulating Cell-Free DNA for the Noninvasive Detection of Colorectal Cancer.

Background: As a crucial epigenetic modification, DNA 5-hydroxymethylcytosine (5-hmC) plays a key role during colorectal cancer (CRC) carcinogenesis. Nevertheless, the levels of 5-hmC-related genes in the circulating DNA of CRC remain largely unknown. Methods and Results: The GSE81314 dataset from the Gene Expression Omnibus (GEO), which was generated by chemical marking-based low-input shotgun sequencing to detect 5-hmC in circulating cell-free DNA (cfDNA) was used in the present study. The GSE81314 dataset includes data for 8 plasma samples from healthy individuals and 4 plasma samples from CRC patients. The difference in the 5-hmC levels in cfDNA between the CRC group and healthy individuals was analyzed by the differentially expressed genes (DEG) package. Weighted gene coexpression network analysis (WGCNA) was conducted to analyze gene coexpression modules associated with sample characteristics. DEG analysis identified 19 upregulated and 9 downregulated 5-hmC-related genes. WGCNA showed that the pink, purple, and brown modules, which contain 531 genes in total, were significantly correlated with CRC (0.66, 0.61, and -0.59, respectively). We used gene set enrichment analysis (GSEA) software to compare 5-hmC-related genes and pathways between CRC patients and healthy controls. We further performed a protein-protein interaction (PPI) analysis and identified 4 nodes (LCN2, LRG1, S100P, and TACSTD2) that played key roles in the network, and we analyzed the expression of these nodes S100P in the GEPIA database. Consistent with the 5-hmC levels in CRC patient plasma, our external validation results from the GEPIA and UALCAN databases showed that LCN2, LRG1, S100P, and TACSTD2 were highly expressed in CRC tissue compared with controls. The DNA promoter methylation levels of LCN2, LRG1, and S100P were lower in CRC tissue than in normal control tissue. Conclusion: The present findings suggest that abnormality in cell-free DNA hydroxylation in plasma may be associated with CRC. In addition, the 5-hmC levels of LCN2, LRG1, S100P, and TACSTD2 in circulating cfDNA may be used as potential noninvasive markers for CRC.

A questionnaire-based study to comprehensively assess the status quo of rare disease patients and care-givers in China.

BACKGROUND: There are over 16.8 million rare disease patients in China, representing a large community that should not be neglected. While the public lack the awareness of their existence and difficult status quo, for one reason that they exist as a rare and special group in our society, for another reason that all sectors of the community haven't introduced and propagandized them suitably. However, as a special group with more difficulties in all aspects than normal healthy persons, they need enough care and love from us. To provide a basis for policy-makers to better understand the status quo of rare disease patients and care-givers in China and to devise some new policies to improve their quality of life, a comprehensive analysis of the status quo, unmet needs, difficulty caused by the rare disease is essential. METHODS: A questionnaire-based online study of patients and care-givers (usually family members) was performed. The questionnaire was composed of 116 questions, such as the diagnosis process, treatment access, financial burden, views on patients' organizations, and a series of standardized tests to assess the quality of their life, including the SF-36, PHQ-9, PHQ-15, GAD-7, and PSQI. To examine the influence of age, disease type, and relationship to patients on the scores in these tests, statistical analysis with a general linear model was conducted. FINDINGS: A total of 1959 patients and care-givers participated in the survey, representing 104 rare diseases, such as lysosomal storage diseases, hemophilia, and muscular dystrophy diseases. The diagnosis was delayed for 1.4 ± 3.0 years, and patients experienced 1.6 ± 3.8 misdiagnoses between 3.2 ± 2.4 hospitals. The hospitals where diagnoses were made were highly concentrated in 10 large hospitals (43.8%) and 5 big cities (42.1%), indicating a significant inequality of medical resources. The disease often led to difficulty in social life, education, and employment, as well as financial burden that was seldom covered by medical insurance. A battery of standardized tests demonstrated poor health status, depression, somatization, anxiety, and sleeping issues among both patients and care-givers (p < 0.05). Statistical analysis of the questionnaire also showed that poor health, anxiety, depression, somatization, and sleeping problems were more prevalent in patients than in care-givers, and more prevalent in more severe diseases (e.g., hemophilia, Dravet) or undiagnosed than in other diseases. INTERPRETATIONS: This study identified the lack of rare disease awareness and legislative support as the major challenge to rare diseases in China, and makes key recommendations for policy-makers, including legislating orphan drug act, raising rare disease awareness, providing sufficient and fair opportunities about education and employment, expanding the medical insurance coverage of treatments, and protecting rights in education and employment.

Establishment and Clinical Application of a Method for Detecting T Lymphocyte Subsets by Cellular Immunochip Technology.

OBJECTIVE: To establish and verify the method for detecting the immune phenotype of peripheral blood T lymphocytes by cellular immune chip technology, analyze the immune status, and discuss its clinical diagnostic value of different populations in the Qingyuan area. METHODS: First, a cellular immune chip was used to detect the number of T lymphocyte subsets CD3+, CD4+, CD8+, and CD4/CD8, followed by evaluating the accuracy and precision through a comparison with flow cytometry. After passing the performance verification, a large-scale detection was performed by a cellular immune chip in 8389 cases. Immunochip technology detects the expression of T lymphocyte subsets and analyzes the differences in cellular immune function among people with physical examination, inflammation, and cancer, as well as different cancer types and in genders. RESULTS: The cell immunochip method and flow cytometry method have the same accuracy and precision in detecting specimens, and the former is fast and simple, and is suitable for clinical use; big data analysis is expected to establish a reference range for CD3+, CD4+, and CD8+ T cell counts in Qingyuan. There are statistical differences in CD3+, CD4+, CD8+ T cell counts in physical examination, inflammation and cancer populations; there are also certain differences in CD3+, CD4+, CD8+ T cell counts and CD4/CD8 ratios between different cancer types and different diseases. CONCLUSION: The method of cell immunochip technology to detect T lymphocyte subsets is simple and practical, with accurate results and rapid detection. It can be used for immune function monitoring and treatment prognosis evaluation of people with different diseases, and it is worthy of popularization and application in clinical practice.

Association of Aldehyde Dehydrogenase 2 Gene Polymorphism with Myocardial Infarction.

OBJECTIVE: This study explored the correlation between myocardial infarction (MI) and the Glu504Lys polymorphism in the aldehyde dehydrogenase 2 (ALDH2) gene in the Qingyuan area. METHODS: The Glu504Lys polymorphism of the ALDH2 gene was analyzed using the polymerase chain reaction and deoxyribonucleic acid microarray analysis for 468 patients diagnosed with MI for the first time and 132 healthy subjects. RESULTS: There was a significant difference in the distribution of the ALDH2 genotype between the MI group and the control group (P = 0.0492), but there was no significant difference in allele frequency between the two groups (P = 0.1363). The clinical data showed that there were statistically significant differences (P < 0.05) in the two groups' gender and age distributions, rates of diabetes and hypertension, levels of alcohol and tobacco use, serological levels of heart markers, blood lipids and glucose. The subgroup analysis of ALDH2 genotypes found that alcohol consumption, high levels of myoglobin, and low levels of high-density lipoprotein cholesterol were significantly associated with a higher incidence of MI (P < 0.05). After adjusting for gender, hypertension, diabetes, and other related influencing factors, logistic regression analysis showed that the ALDH2 genotype GA/AA was an independent risk factor for MI (P < 0.05, OR = 1.479, 95% CI = 1.003-2.179). CONCLUSION: The presence of risk alleles with the genetic effect (ALDH2 genotype GA/AA) is an independent risk factor for MI.

Emerging Biological Functions of IL-17A: A New Target in Chronic Obstructive Pulmonary Disease?

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease that causes high rates of disability and mortality worldwide because of severe progressive and irreversible symptoms. During the period of COPD initiation and progression, the immune system triggers the activation of various immune cells, including Regulatory T cells (Tregs), dendritic cells (DCs) and Th17 cells, and also the release of many different cytokines and chemokines, such as IL-17A and TGF-ß. In recent years, studies have focused on the role of IL-17A in chronic inflammation process, which was found to play a highly critical role in facilitating COPD. Specially, IL-17A and its downstream regulators are potential therapeutic targets for COPD. We mainly focused on the possibility of IL-17A signaling pathways that involved in the progression of COPD; for instance, how IL-17A promotes airway remodeling in COPD? How IL-17A facilitates neutrophil inflammation in COPD? How IL-17A induces the expression of TSLP to promote the progression of COPD? Whether the mature DCs and Tregs participate in this process and how they cooperate with IL-17A to accelerate the development of COPD? And above associated studies could benefit clinical application of therapeutic targets of the disease. Moreover, four novel efficient therapies targeting IL-17A and other molecules for COPD are also concluded, such as Bufei Yishen formula (BYF), a Traditional Chinese Medicine (TCM), and curcumin, a natural polyphenol extracted from the root of Curcuma longa.

An analysis of the correlation between the human apolipoprotein E gene polymorphism and lipoprotein-associated phospholipase A2.

BACKGROUND: Atherosclerosis is one of the most common cardiovascular and cerebrovascular diseases. This study aimed to explore the correlation between gene polymorphism of human apolipoprotein E (ApoE) and lipoprotein-associated phospholipase A2 (Lp-PLA2). METHODS: A total of 220 patients with atherosclerotic cardiovascular disease who were treated in our hospital from June 2016 to March 2017 were enrolled in this study and assigned as the atherosclerotic cardiovascular disease group and 193 patients who were treated contemporaneously in our hospital but had no atherosclerotic cardiovascular disease were enrolled and assigned as the control group. Gene polymorphism of ApoE was detected by PCR-fluorescent probe technique and the level of Lp-PLA2 was detected by ELISA. RESULTS: There were a total of 5 genotypes of ApoE in these two groups, which were E2/3, E3/3, E3/4, E2/4, and E4/4. E2/2 was not found in any of the patients. E3/3 made up the majority in both groups. There was no significant difference between the proportion of genotypes and frequencies of alleles in the two groups (P>0.05). There was no difference between LP-PLA2 among the different genotypes in these two groups (P>0.05). CONCLUSIONS: We cannot conclude that ApoE gene polymorphism is related to atherosclerotic cardiovascular and cerebrovascular diseases. And it cannot be concluded that ApoE gene polymorphism is related to Lp-PLA2 level.

Metabolic reprogramming-based characterization of circulating tumor cells in prostate cancer.

BACKGROUND: Circulating tumor cells (CTCs), an advantageous target of liquid biopsy, is an important biomarker for the prognosis and monitoring of cancer. Currently, detection techniques for CTCs are mainly based on the physical and/or epithelial characteristics of tumor cells. However, biofunctional activity markers that can indicate the high metastatic capacity of CTCs are lacking. METHODS: Functional microarray, quantitative real-time polymerase chain reaction, and Western blot were used on five prostate cancer cell lines with different metastatic capacities to identify the metastasis-related metabolic genes. The identified genes were detected in the CTCs of 64 clinical samples using the RNA in situ hybridization. A multi-criteria weighted model was used to determine the optimal metabolic markers for the CTCs test. Based on five fluorescent signals targeting DAPI, CD45, metabolic, epithelial (EpCAM/CKs), and mesenchymal (Vimentin/Twist) markers, the filtration-enriched CTCs were classified as GM+CTCs/GM-CTCs (metabolic types) or E-CTCs/H-CTCs/M-CTCs (EMT types). Correlation analysis and ROC curve were conducted on 54 prostate cancer samples to evaluate the clinical significance of CTCs subtypes. RESULTS: Eight metastasis-related metabolic genes were identified, including HK2, PDP2, G6PD, PGK1, PHKA1, PYGL, PDK1, and PKM2. Among them, PGK1 and G6PD were determined as optimal glucose metabolic (GM) markers for CTCs. GM+CTCs (marked by PGK1/G6PD) were detectable in 64.8% (35/54) of prostate cancer patients, accounting for 46.5% (134/288) of total CTCs. An increased GM+CTCs level was associated with advanced tumor stage and metastasis (P <  0.05). In the discrimination of cancer metastasis from non-metastasis, GM+CTCs presented a higher AUC of the ROC curve (0.780) compared with the EMT CTCs subtypes (E-CTCs 0.729, H-CTCs 0.741, and M-CTCs 0.648). A triple tPSA-Gleason-GM+CTCs marker increased the AUC to 0.904, which was better than that of the tPSA-Gleason-H-CTCs marker (0.874). CONCLUSIONS: The metabolic marker (PGK1/G6PD) is determined as the indicator for the biofunctional activity analysis of CTCs, compared with the existing morphological (EMT) classification on CTCs. The metabolic characterization of CTCs demonstrates that hypermetabolic GM+CTCs are promising biomarkers for prostate cancer metastasis.

Long non-coding RNA UBE2CP3 enhances HCC cell secretion of VEGFA and promotes angiogenesis by activating ERK1/2/HIF-1α/VEGFA signalling in hepatocellular carcinoma.

BACKGROUND: Angiogenesis is considered as an important process in the development of malignancies and is associated with cancer progression and metastasis. Hepatocellular carcinoma (HCC) is the most common primary tumor of the liver and is recognized as a typical angiogenic tumor. Thus, it is of great importance to study the underlying mechanism of angiogenesis in HCC. The long non-coding RNA (lncRNA) ubiquitin conjugating enzyme E2C pseudogene 3 (UBE2CP3) has been reported as an oncogene that promotes tumor metastasis in HCC. However, the role and underlying mechanisms of UBE2CP3 in HCC angiogenesis are still unclear. METHODS: We measured the expression levels of UBE2CP3 by in situ hybridization (ISH) and quantitative real-time polymerase chain reaction (qRT-PCR) in HCC patient samples. We also concomitantly used CD31/PAS double-staining to measure endothelial vessel (EV) density and used qRT-PCR to measure the CD31 mRNA level. HepG2 and SMMC-7721 cells were transfected with Lv-UBE2CP3 or Sh-UBE2CP3 virus to obtain stably over-expressing or knocking-down UBE2CP3 cell lines. The indirect effects of UBE2CP3 on ECs were studied by establishing a co-culture system using Transwell chambers with a 0.4-µm pore size. HCC cells and ECs in the co-culture system were separated, but the cytokines and growth factors were able to communicate with each other. Following exposed to HCC cells, ECs were collected for functional studies. Finally, we studied the function of UBE2CP3 in vivo by chick embryo chorioallantoic membrane (CAM) angiogenesis assays and nude mouse tumorigenicity assays. RESULTS: In this study, we found that UBE2CP3 expression was higher in HCC tissues than in para-tumor tissues and was up-regulated in tissues with high EV density. Functionally, we found that in the co-culture systems, HCC cells overexpressing UBE2CP3 promoted HUVEC proliferation, migration and tube formation via the activation of ERK/HIF-1α/p70S6K/VEGFA signalling, increasing the level of VEGFA in HCC cell supernatant. In addition, the opposite results appeared when the expression of UBE2CP3 in HCC cells was knocked down. Consistent with these results, CAM angiogenesis assays and nude mouse tumorigenicity assays showed that UBE2CP3 expression up-regulated EV density in vivo. CONCLUSION: Our study suggests that UBE2CP3 can enhance the interaction between HCC tumor cells and HUVECs and promote HCC tumorigenicity by facilitating angiogenesis.

Long non-coding RNA UBE2CP3 promotes tumor metastasis by inducing epithelial-mesenchymal transition in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a highly aggressive, solid malignancy that has a poor prognosis. Long non-coding RNAs (lncRNAs) have been found to be dysregulated in various cancers, including HCC. However, the molecular mechanism involving lncRNAs in HCC remains largely unknown. In this study, lncRNAs differentially expressed between HCC and corresponding non-cancerous tissue were identified by microarray analysis. A specific differentially expressed lncRNA UBE2CP3 (ubiquitin conjugating enzyme E2 C pseudogene 3) was identified. LncRNA UBE2CP3 was frequently up-regulated in HCC samples as assessed by quantitative real-time polymerase chain reaction (qRT-PCR) and in situ hybridization (ISH) experiments. Clinical data showed that high levels of lncRNA UBE2CP3 were correlated with poor prognosis in HCC patients. Functional studies demonstrated that over-expression of lncRNA UBE2CP3 promoted cell invasion and migration in vitro and in vivo. Mechanistically, enhanced expression of lncRNA UBE2CP3 increased the expression of Snail1 and N-cadherin, but decreased the expression of E-cadherin, thus promoting the process of epithelial to mesenchymal transition (EMT) and finally inducing cell invasion and migration. Furthermore, serum levels of lncRNA UBE2CP3 were increased in HCC patients and decreased after surgery. Our results suggest that lncRNA UBE2CP3 promotes the metastasis of HCC and that serum lncRNA UBE2CP3 may be a new biomarker for the diagnosis of HCC.