Expression Of Highly Upregulated In Liver Cancer Research Articles

Qntrolling the LncRNA HULC-Tregs-PD-1 axis inhibits immune escape in the tumor microenvironment

BackgroundImmune escape remains a major challenge in the treatment of malignant tumors. Here, we studied the mechanisms underlying immune escape in the tumor microenvironment and identified a potential therapeutic target. MethodsPathological specimens from patients with liver cancer, soft tissue sarcoma, and liver metastasis of colon cancer were subjected to immunohistochemistry analysis to detect the expression of programmed death-1 (PD-1) in the tumor microenvironment (TME). Additionally, the expression of regulatory T cells (Tregs) and long non-coding RNAs (lncRNAs), such as highly upregulated in liver cancer (HULC) was evaluated by fluorescence in situ hybridization, and the relationship between HULC, Treg cells, and PD-1 was determined. The animals were divided into H22 hepatic carcinoma and S180 sarcoma groups. Each group was divided into Foxp3−/-C57BL/6J and C57BL/6J mice. Thereafter, mice were inoculated with 0.1 ml S180 sarcoma cells or 0.1 ml H22 hepatoma cells, at a concentration of 1 × 107/ml. The number of splenic CD4+CD25+Foxp3+ T cells was detected by flow cytometry, and serum interleukin-10 (IL-10) and transforming growth factor β1 (TGF-β1) levels were detected using a Luminex liquid suspension chip. Expression of PD-1, fork head box P3 (Foxp3), and HULC in the TME, were analyzed and the therapeutic effect of inhibiting the lncRNA HULC-Treg-PD-1 axis in malignant tumors was determined. ResultsHigh expression of lncRNA HULC promotes the proliferation of Treg cells and increases PD-1 expression in the tumor microenvironment. The HULC-Treg-PD-1 axis plays an immunosuppressive role and promotes the proliferation of malignant tumors. Knocking out the Foxp3 gene can affect the HULC-Treg-PD-1 axis and reduce PD-1, IL-10, and TGF-β1 expression to control the growth of malignant tumors. ConclusionThe lncRNA HULC-Treg-PD-1 axis promotes the growth of malignant tumors. This axis could be modulated to reduce PD-1, IL-10, and TGF-β1 expression and the subsequent immune escape. The inhibition of immune escape in the tumor microenvironment can be achieved by controlling the LncRNA HULC-Treg-PD-1 axis.

Long noncoding RNA HULC regulates the NF-κB pathway and represents a promising prognostic biomarker in liver cancer.

Long noncoding RNAs (lncRNAs) are involved in a diverse array of biological processes. While lncRNAs are commonly upregulated in hepatocellular carcinoma (HCC), the specific regulatory roles they play in this oncogenic context require further study and clarification. Although HULC (lncRNA highly upregulated in liver cancer) is involved in disease pathogenesis, its precise role in this context remains unclear. Here, we have explored the mechanistic relevance of HULC expression by assessing its expression in patient samples. The importance of this lncRNA in the onset and progression of HCC was investigated through in vitro approaches including Western blotting, quantitative PCR, Transwell assays, electron microscopy, wound healing assays, and real-time cell analysis (RTCA). Additionally, the in vivo functions of this lncRNA were assessed using an orthotopic HCC xenograft in nude mouse model system. HULC was identified as a lncRNA that is highly upregulated in human liver tumors. In vitro, HULC was able to promote HCC malignancy, although its excess overexpression also led robust autophagic induction, promoting the increased expression of autophagy-associated genes including LC3 and Beclin-1. At a mechanistic level, HULC was able to promote the phosphorylation of p65 and IkBkB thus enhancing autophagy by increasing LC3II levels in a manner dependent upon the NF-κB pathway. HULC downregulation was also linked to impaired orthotopic HCC tumor growth in vivo. The link between HULC and autophagy may play a role in disease progression. These results suggest that HULC is an oncogenic lncRNA, and may thus offer value as a prognostic biomarker and promoter of HCC development, in addition to being a potential therapeutic target in this cancer type.

Potential role of lncRNA HULC/miR‑128‑3p/RAC1axis in the inflammatory response during LPS‑induced sepsis in HMEC‑1 cells.

Sepsis is a serious clinical condition characterized by systemic inflammation. The long noncoding RNA (lncRNA) highly upregulated in liver cancer (HULC) was validated to partake in the development of sepsis. The present study aimed to investigate the potential mechanism of HULC in lipopolysaccharide (LPS)-induced sepsis. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis was employed to examine the expression of HULC, microRNA (miR)-128-3p, Rac family small GTPase 1 (RAC1) and pro-inflammatory factors [IL-6, TNF-α, intercellular adhesion molecule (ICAM1) and vascular cell adhesion molecule (VCAM1)] in the serum of patients with sepsis or LPS-induced human dermal microvascular endothelial cells (HMEC-1). Flow cytometry and western blot assays were performed to detect cell apoptosis. The targeted relationship among HULC, miR-128-3p and RAC1 was confirmed by a dual-luciferase reporter assay, RNA binding protein immunoprecipitation (RIP) assay and RNA pull-down assay. HULC and RAC1 were found to be upregulated, and miR-128-3p was downregulated in the serum of patients with sepsis and LPS-stimulated HMEC-1 cells. LPS promoted apoptosis and inflammation, which were decreased by silencing of HULC. HULC targeted miR-128-3p and negatively regulated its expression. HULC knockdown protected HMEC-1 cells from LPS-induced injury by upregulating miR-128-3p. RAC1 was a target of miR-128-3p, and gain of RAC1 also relieved the silencing of HULC-mediated suppressive effects on apoptosis and inflammation in LPS-stimulated HMEC-1 cells. In conclusion, HULC knockdown partially reversed LPS-induced sepsis via the regulation of miR-128-3p/RAC1 axis.

Study of long non-coding RNA highly upregulated in liver cancer (HULC) in breast cancer: A clinical & in vitro investigation.

Background & objectives:Breast cancer remains the most common malignancy among women worldwide. Long non-coding RNAs (lncRNAs) have been shown to play critical roles in tumour initiation and progression. This study was aimed to evaluate the potential role of lncRNA highly upregulated in liver cancer (HULC) in breast cancer.Methods:The expression of HULC was evaluated in breast cancer patients and cell lines using real-time quantitative reverse transcription polymerase chain reaction. Small interfering RNA-based knockdown was also employed to study the potential role of HULC in breast cancer cell lines including ZR-75-1, MCF7 and MDA-MB-231.Results:HULC was significantly upregulated in tumour tissues compared to non-tumoural margins (P<0.001). The receiver operating characteristic (ROC) curve analysis demonstrated the biomarker potential of HULC (ROCAUC=0.78, P<0.001). The HULC knockdown induced apoptosis and suppressed cellular migration in breast cancer cell lines.Interpretation & conclusions:Our results indicated that HULC was upregulated in breast cancer and might play a role in tumourigenesis. The HULC may have a potential to be exploited as a new biomarker and therapeutic target in breast cancer.

Circulating extracellular vesicle-encapsulated HULC is a potential biomarker for human pancreatic cancer.

The role of long noncoding RNAs (lncRNAs) in the epithelial‐mesenchymal transition (EMT) in pancreatic ductal adenocarcinoma (PDAC) is unclear. Some lncRNAs can be transferred by extracellular vesicles (EVs) and have potential as biomarkers. Here, we identify an lncRNA that could serve as a biomarker for PDAC and show the functional roles of the lncRNA. Expression profiling of lncRNAs revealed that highly upregulated in liver cancer (HULC) was highly expressed, and induced, by transforming growth factor‐β in PDAC cells and their EVs. Knockdown of HULC decreased PDAC cell invasion and migration by inhibiting the EMT. Thus, HULC could be transferred by EVs, and promote EMT, invasion, and migration in recipient PDAC cells. To assess the roles of HULC, PDAC cell xenografts in nude mice were established. Knockdown of HULC in PDAC cells implanted in mice inhibited tumor growth. Moreover, microRNA‐133b suppressed PDAC cell invasion and migration by inhibiting the EMT through targeting HULC. Furthermore, serum samples were obtained from 20 PDAC and 22 intraductal papillary mucinous neoplasm (IPMN) patients, as well as 21 healthy individuals. Analysis of serum EV HULC expression by digital PCR showed that HULC expression was significantly increased in PDAC patients compared to healthy individuals or IPMN patients. Additionally, HULC showed good predictive performance for discriminating PDAC, suggesting that the analysis of EV‐encapsulated HULC would contribute to the diagnosis for human PDAC. Extracellular vesicle‐transported HULC promotes cell invasion and migration by inducing the EMT, and microRNA‐133b suppresses the EMT by targeting HULC. Extracellular vesicle‐encapsulated HULC could be a potential circulating biomarker for human PDAC.

LncRNA HULC promotes the progression of gastric cancer by regulating miR-9-5p/MYH9 axis

Long non-coding RNAs (lncRNAs) highly upregulated in liver cancer (HULC) has been identified as an oncogene involved in many human cancers. Herein, we aimed to further explore the role and molecular mechanism of HULC in gastric cancer (GC) progression. The levels of HULC, miR-9-5p and myosin heavy chain 9 (MYH9) mRNA were detected by qRT-PCR. The targeted interaction between HULC and miR-9-5p was verified by dual-luciferase reporter and RNA pull-down assays. Cell proliferation assay, cell colony formation, flow cytometry and transwell assay were used to determine cell proliferation, colony formation, apoptosis and migration and invasion, respectively. Xenograft assay was used to observe the effect of HULC on GC growth in vivo. Our results revealed that HULC was upregulated and miR-9-5p was downregulated in GC, and both were associated with clinicopathologic features of GC patients. A positive correlation was found between HULC expression and epithelial-to-mesenchymal transition (EMT) of GC tissues. Moreover, HULC repressed miR-9-5p expression by binding to miR-9-5p. The regulatory effects of HULC knockdown on GC cell proliferation, migration, invasion, EMT and apoptosis were reversed by introduction of anti-miR-9-5p. HULC regulated MYH9 expression by acting as a molecular sponge of miR-9-5p in GC cells. HULC knockdown inhibited tumor growth in vivo. In conclusion, our data demonstrated that HULC knockdown repressed GC progression at least partly by regulating miR-9-5p/MYH9 axis.

Long non-coding RNA highly up-regulated in liver cancer promotes exosome secretion.

BACKGROUNDHighly upregulated in liver cancer (HULC) is a long non-coding RNA (lncRNA) which has recently been identified as a key regulator in hepatocellular carcinoma (HCC) progression. However, its role in the secretion of exosomes from HCC cells remains unknown.AIMTo explore the mechanism by which HULC promotes the secretion of exosomes from HCC cells.METHODSSerum and liver tissue samples were collected from 30 patients with HCC who had not received chemotherapy, radiotherapy, or immunotherapy before surgery. HULC expression in serum exosomes and liver cancer tissues of patients was measured, and compared with the data obtained from healthy controls and tumor adjacent tissues. The effect of HULC upregulation in HCC cell lines and the relationship between HULC and other RNAs were studied using qPCR and dual-luciferase reporter assays. Nanoparticle tracking analysis was performed to detect the quantity of exosomes.RESULTSHULC expression in serum exosomes of patients with HCC was higher than that in serum exosomes of healthy controls, and HULC levels were higher in liver cancer tissues than in tumor adjacent tissues. The expression of HULC in serum exosomes and liver cancer tissues correlated with the tumor-node-metastasis (TNM) classification, and HULC expression in tissues correlated with that in serum exosomes. Upregulation of HULC promoted HCC cell growth and invasion and repressed apoptosis. Notably, it also facilitated the secretion of exosomes from HCC cells. Moreover, qPCR assays showed that HULC repressed microRNA-372-3p (miR-372-3p) expression. We also identified Rab11a as a downstream target of miR-372-3p. Dual-luciferase reporter assays suggested that miR-372-3p could directly bind both HULC and Rab11a.CONCLUSIONOur findings illustrate the importance of the HULC/miR-372-3p/Rab11a axis in HCC and provide new insights into the molecular mechanism regulating the secretion of exosomes from HCC cells.

LncRNA HULC promotes lung squamous cell carcinoma by regulating PTPRO via NF-κB.

Accumulating studies have implicated that long noncoding RNA (lncRNA) plays a vital role in lung cancer. However, little is known of the role of lncRNA highly upregulated in liver cancer (HULC) in the pathogenesis of lung squamous cell carcinoma (LSCC). In this study, we investigated the modifying effects and underlying mechanisms of lncRNA HULC in LSCC. Significantly decreased level of lncRNA HULC was observed in LSCC samples compared with adjacent tissues. Besides, the expression of lncRNA HULC was negatively associated with protein tyrosine phosphatase receptor type O (PTPRO) in LSCC. Moreover, lncRNA HULC could promote the proliferation of LSCC cells by downregulating the expression PTPRO dependent on the phosphorylation and activation of nuclear factor-κB (NF-κB). The present study firstly shows strong evidence supporting a critical role of lncRNA HULC in promoting LSCC by regulating PTPRO/NF-κB signaling pathway, which provides new promising biomarkers for LSCC.

Hepatocellular carcinoma up-regulated long non-coding RNA: a putative marker in multiple sclerosis.

Highly up-regulated in liver cancer (HULC) is a cancer-associated long non-coding RNA (lncRNA) which may regulate expression of other genes by working as a competing RNA for microRNAs. In the current study, we assessed transcript levels of this lncRNA in peripheral blood of multiple sclerosis (MS) patients and healthy persons to evaluate its possible role in the pathogenesis of this inflammatory disease and its diagnostic power. The results of Multilevel Bayesian showed no significant difference between cases and controls (P = 0.002, 95% confidence interval (CI) = [3.08, 13.3]). However, based on the results of Quantile regression, there was a significant difference in HULC expression between cases and controls after controlling the effects of sex and age (P = 0.002, 95% CI = [3.08, 13.3]) which shows different trends in males and females. HULC expression was inversely correlated with age of male subjects but not female subjects. HULC transcript levels had 91.1% accuracy in diagnosis of MS disease (Specificity: 80%, Sensitivity: 86.6%). The diagnostic power of HULC was higher in male subjects aged less than 50years (AUC = 0.923, Specificity: 80%, Sensitivity: 100%). The present study shows the possibility of application of transcript levels of HULC as diagnostic marker in MS disease. However, future studies with larger sample sizes are necessary to validate our results.

HULC functions as an oncogene in ovarian carcinoma cells by negatively modulating miR-125a-3p.

The aberrant expression of highly upregulated in liver cancer (HULC) has been reported to participate in ovarian cancer development. A recent research has revealed that HULC-modulated microRNAs (miRNAs) in tumorigenesis. To confirm the functions of HULC on tumorigenesis of ovarian, we explored the effects of HULC expression on ovarian cancer cell development, as well as the underlying mechanism. We transfected SKOV3 cells with pEX-HULC, sh-HULC, and miR-125a-3p mimic as well as their corresponding negative controls (pEX-3, sh-NC, and NC) to alter the expression of HULC and miR-125a-3p, which were analyzed by quantitative reverse transcription PCR (qRT-PCR). Expression of proteins associated with cell cycle, apoptosis, and signaling pathways was determined by Western blot assay. The proliferation, apoptosis, migration, and invasion were explored by bromodeoxyuridine (BrdU) incorporation assay, Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) method, and transwell migration and invasion assays, respectively. HULC overexpression promoted proliferation, migration, and invasion, while inhibited apoptosis of SKOV3 cells. In addition, HULC negatively regulated the expression of miR-125a-3p. Besides, miR-125a-3p mimic reversed the effects of HULC on proliferation, migration, and invasion as well as apoptosis of SKOV3 cells. Moreover, we found that HULC enhanced phosphorylated expression of regulatory factors in phosphatidylinositol 3 kinase/protein kinase B/mammalian targets of rapamycin (PI3K/AKT/mTOR) signaling pathway by downregulating expression of miR-125a-3p. Overexpression of HULC promoted ovarian carcinoma development by activating PI3K/AKT/mTOR signaling pathway via downregulating miR-125a-3p.

Involvement of long non-coding RNA HULC (highly up-regulated in liver cancer) in pathogenesis and implications for therapeutic intervention

ABSTRACTIntroduction: HULC (highly upregulated in liver cancer) is a long non-coding RNA (lncRNA) which is, as its name suggests, highly upregulated in hepatocellular carcinoma and in several other cancers. Increased HULC expression levels are strongly associated with clinicopathologic features such as tumor stages and overall survival and is a driver of tumor proliferation, migration, and invasion.Areas covered: This review addresses the discovery of HULC and discusses the consequences of HULC deregulation in cancer, the underlying molecular mechanisms and the potential of HULC as a biomarker and therapeutic target.Expert opinion: HULC is a promising candidate as a therapeutic target in cancer; however, more studies are necessary to further elucidate the underlying molecular mechanism(s), especially in cancer types other than hepatocellular carcinomas. Future studies that focus on an optimized HULC-targeting approach are necessary to clarify the best strategy to target this lncRNA in vivo and in patients.Trial registration: ClinicalTrials.gov identifier: NCT02641847.Trial registration: ClinicalTrials.gov identifier: NCT03469544.Trial registration: ClinicalTrials.gov identifier: NCT03057171.Trial registration: ClinicalTrials.gov identifier: NCT02948855.Trial registration: ClinicalTrials.gov identifier: NCT03000764.Trial registration: ClinicalTrials.gov identifier: NCT02221999.

Long non-coding RNA highly up-regulated in liver cancer promotes epithelial-to-mesenchymal transition process in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is an oral and maxillofacial malignancy that exhibits high incidence worldwide. In diverse human cancers, the long non‐coding RNA (lncRNA) highly up‐regulated in liver cancer (HULC) is aberrantly expressed, but how HULC affects OSCC development and progression has remained mostly unknown. We report that HULC was abnormally up‐regulated in oral cancer tissues and OSCC cell lines, and that suppression of HULC expression in OSCC cells not only inhibited the proliferation, drug tolerance, migration and invasion of the cancer cells, but also increased their apoptosis rate. Notably, in a mouse xenograft model, HULC depletion reduced tumorigenicity and inhibited the epithelial‐to‐mesenchymal transition process. Collectively, our findings reveal a crucial role of the lncRNA HULC in regulating oral cancer carcinogenesis and tumour progression, and thus suggest that HULC could serve as a novel therapeutic target for OSCC.

Long non-coding RNA HULC affects the proliferation, apoptosis, migration, and invasion of mesenchymal stem cells.

Exploring the molecular mechanisms of growth and function in MSCs is the key to improve their clinical therapeutic effects. Currently, more and more evidence show that the long non-coding RNA (lncRNA) plays an important role in the growth, stemness and function of MSCs.Both HULC and MALAT1 are the earliest discovered LNCRNAs, which are closely related to tumor growth. All of them can promote the growth of liver cancer stem cells. Previously, we have studied the effects of MALAT1 on the growth and function of MSCs. In this study, we focused on the effects of HULC on MSCs. We elucidated the effects of HULC on the growth and differentiation of MSCs, and explored the relationship between inflammatory stimuli and HULC expression in MSCs. Our findings provide a new molecular target for the growth and clinical application of MSCs.

Long non-coding RNA HULC affects downstream-related targets to regulate migration and invasion of hepatoma cells

Objective: To investigate the effects of long non-coding RNA HULC on downstream related targets regulating the migration and invasion of hepatoma cells and theirs mechanism of action. Methods: The expression of highly upregulated in liver cancer (HULC) in hepatocellular carcinoma, and adjacent normal liver tissues and different hepatocellular carcinoma cells were detected by qPCR. The correlation between clinicopathological data of HULC and liver cancer patients were analyzed. Dual-luciferase reporter gene detected the interaction between HULC and miR-186. CCK-8 assay was used to detect the effect of HULC on proliferation of hepatocellular carcinoma cells. The change in hepatocellular carcinoma cell invasions ability after HULC inhibition was detected by transwell invasion assay and migration ability after inhibition of HULC was assessed by scratch assay. Differences between groups were compared using one-way ANOVA. P < 0.05 was considered statistically significant. Results: Compared with adjacent normal liver tissue, the expression of HULC in hepatocellular carcinoma was significantly higher [(1.79 ± 0.25) vs. (0.23 ± 0.05), P < 0.05]. The expression level of HULC was highest in hepatocellular carcinoma HepG3 cells. HULC specifically banded to the 3'UTR of miR-186 and regulated the expressional activity of miR-186. After inhibiting the expression of HULC, the proliferation of hepatocellular carcinoma cells was 72 h (0.35 ± 0.09) vs. (0.82 ± 0.16), P < 0.05; 96 h (0.42 ± 0.08) vs.(1.28 ± 0.19), P < 0.05), and the ability of migration and invasion was relatively decreased in 24 h (11.2% ± 1.6%) vs. (23.5% ± 3.6%), P < 0.05; 48 h (18.6% ± 3.0%) vs. (38.6% ± 5.6%), P < 0.05; 72 h (43.6% ± 5.3% ) vs. (69.6% ± 7.6%), P < 0.05]. After inhibiting the expression of HULC, the tumor volume and body weight of tumor-bearing mice were significantly reduced [volume (2.89 ± 0.29) cm(3) vs. (0.89 ± 0.18) cm(3), P < 0.05, body weight (3.18 ± 0.41) g vs. (0.45 ± 0.09) g, P < 0.05]. Conclusion: HULC plays an important role in the occurrence and development of hepatocellular carcinoma and can influence the biological behavior of hepatoma cells by regulating the expression of downstream-related targets.

LncRNA HULC promotes epithelial and smooth-muscle-like differentiation of adipose-derived stem cells by upregulation of BMP9.

Adipose-derived stem cells (ADSCs), a source of mesenchymal stem cells, are able to differentiate into numerous cell lineages, including epithelial and smooth muscle cells. The use of ADSCs in tissue engineering technology has become the most promising therapeutic approach for urethral reconstruction. This study aimed to explore the effect of lncRNA highly upregulated in liver cancer (HULC) on the induction of ADSCs to differentiate into epithelial and smooth-muscle-like cells. ADSCs were isolated from a male dog, and the expression of HULC in ADSCs was overexpressed by transfection with HULC expressing vector lentivirus. The transfected ADSCs were then incubated with 5 μM ATRA or 2.5 ng/ml TGF-β1 and 5 ng/ml PDGF-BB for 21 days. The expression of epithelial differentiation and smooth-muscle-like differentiation markers were monitored. Besides, cross-regulation between HULC and BMP9 was detected in the differentiated epithelial cells and smooth-muscle-like cells. HULC increased cell viability of ADSCs, but has no impact on ADSCs apoptosis. HULC promotes ADSCs to differentiate into epithelial and smooth-muscle-like cells, as evidenced by the increases in the expression of Uroplakin-II, AE1/AE3, α-SMA, SM-MHC, Calponin, and SM-22α. In addition, HULC could positively regulate BMP9, and BMP9 silence abolished HULC-promoted ADSC's differentiation. Furthermore, HULC activated Wnt/β-catenin pathway while deactivated Notch pathway. HULC was demonstrated to be a promoter during the epithelial and smooth-muscle-like differentiation of ADSCs via the BMP9/Wnt/β-catenin/Notch network. This study provides the first in vitro evidence that HULC-based therapy could be a valuable approach to promote urethral reconstruction.

LncRNA HULC mediates radioresistance via autophagy in prostate cancer cells.

Prostate cancer (PCa) is the second leading cause of cancer death in men. Irradiation is one of the available options for treatment of PCa, however, approximately 10–45% of PCa are resistant to irradiation. We aimed to explore the role of long non-coding RNA highly upregulated in liver cancer (HULC) in the sensitivity of PCa cells to irradiation. Survival rate, cell apoptosis, cycle, expressions of related proteins, and caspase-3 activity were assessed to explore the effects of HULC on sensitivity of PCa cells to irradiation. Expression of HULC in DU-145, PC3, LNCaP, and RWPE-1 cells was determined and the influence of HULC on DU-145 cells was explored. Then, PC3 cells aberrantly expressing HULC were implanted into NOD-SCID mice for tumor xenograft study. Changes of autophagy after aberrant expression of HULC in vivo and in vitro were tested. Furthermore, the interacted protein of HULC and involved signaling pathway were investigated. In PC3 and LNCaP cells under irradiation, survival rate and cell cycle were decreased and apoptosis was increased by HULC knockdown. HULC knockdown arrested PC3 cells at G0/G1 phase. DU-145 was sensitive to irradiation, and resistance to irradiation of DU-145 cells was enhanced by HULC overexpression. Moreover, HULC knockdown enhanced the sensitivity of PC3 xenografts to irradiation. HULC knockdown promoted autophagy through interaction with Beclin-1 and inhibition of mTOR, resulting in increased apoptosis. HULC knockdown improved sensitivity of PCa cells to irradiation both in vivo and in vitro. HULC suppressed Beclin-1 phosphorylation, thereby reduced autophagy, involving the mTOR pathway.

The Significance of Long Non-coding RNA HULC in Predicting Prognosis and Metastasis of Cancers: a Meta-Analysis.

Long non-coding RNAs (lncRNAs) have been demonstrated that they not only play important roles in tumorgenicity but also associate with cancer prognosis. Recently, highly up-regulated in liver cancer (HULC) is abnormally expressed in liver cancer and other cancers, and participated in cancers progression; however, it is unclear whether its expression is associated with prognosis. Here, we performed a meta-analysis and systematic review to evaluate the prognostic value and metastasis of HULC in various cancer patients. The meta-analysis was performed using a systematic search of PubMed, Web of Science, ScienceDirect and Wiley Online Library database to eligible studies. The pooled hazard ratios (HRs) with a 95% confidence interval (95% CI) were calculated to assess its prognosis and metastasis in human cancer. A total of 1134 patients from 11 studies were included. The results indicated that overexpression of HULC was associated with poor overall survival (OS) (HR=1.89, 95% CI: 1.32-2.47). Furthermore, subgroup analysis showed that cancer type (digestive system cancer or non-digestive system cancers) and sample size (more or less than 100) significantly associated between HULC and OS. In addition, overexpression of HULC expression was significantly associated with metastasis in cancers (HR=2.67, 95% CI: 0.94-4.39). The meta-analysis indicated that lncRNA HULC could serve as a new molecular marker for cancer prognosis and metastasis.

The lncRNA HULC functions as an oncogene by targeting ATG7 and ITGB1 in epithelial ovarian carcinoma

Highly upregulated in liver cancer (HULC) is a long noncoding RNA (lncRNA), which has recently been identified as a key regulator in the progression of hepatocellular carcinoma, gliomas and gastric cancer. However, its role in epithelial ovarian carcinoma (EOC) remains unknown. In this study, HULC expression was examined in EOC, borderline and benign ovarian tumors, and normal ovarian tissues by RT-PCR. Ovarian cancer cell phenotypes, as well as autophagy-associated proteins were examined after HULC overexpression or downregulation by plasmid or small interfering RNA (siRNA) transfection, respectively. LncRNA–protein interactions were examined by ribonucleoprotein immunoprecipitation (RIP) assays. We found that HULC expression levels were higher in EOC tissues than normal samples. HULC overexpression induced cell proliferation, migration, invasion, whereas reduced cell apoptosis in vitro and induced tumor growth in vivo. In contrast, downregulation of HULC by siRNA transfection reduced cell proliferation, migration and invasion, and induced cell apoptosis and autophagy. Our results showed that HULC overexpression reduced ATG7, LC3-II and LAMP1 expression, while inducing SQSTM1 (P62) and ITGB1 expression. HULC downregulation had the opposite effects. Furthermore, RIP indicated that ATG7 interacted with HULC; ATG7 downregulation also induced cell proliferation, reduced apoptosis and inhibited autophagy in vitro by reducing LC3-II and LAMP1 expression, while inducing SQSTM1 expression. Furthermore, ATG7 co-transfection with HULC reversed the oncogenic effects of HULC both in vitro and in vivo; however, downregulating ATG7 did not affect cell migration and invasive ability. We found that ITGB1 siRNA co-transfection with HULC reversed the function of HULC in inducing ovarian cancer cell migration and invasive ability. Taken together, our results show that HULC may promote ovarian carcinoma tumorigenesis by inhibiting ATG7 and inducing progression by regulating ITGB1.

Knockdown of lncRNA HULC inhibits proliferation, migration, invasion, and promotes apoptosis by sponging miR-122 in osteosarcoma.

Osteosarcoma is a rare malignant bone tumor with high degree of malignancy. HULC (highly upregulated in liver cancer), a long noncoding RNA (lncRNA) was involved in hepatocellular carcinoma development and progression, but its underlying mechanism in osteosarcoma is unknown. The aim of this study was to explore the functional role of HULC in osteosarcoma. The study was conducted in human osteosarcoma cell lines and the expression of HULC in the cell lines was detected by qRT-PCR. Furthermore, the effects of HULC on tumorigenicity of osteosarcoma cells were evaluated by in vitro assays. Results revealed that HULC was highly expressed in osteosarcoma MG63 and OS-732 cells compared to osteoblast hFOB1.19 cells. Suppression of HULC in osteosarcoma cells inhibited cell viability, migration, invasion, and promoted apoptosis. HULC functioned as an endogenous sponge for miR-122, and its silence functioned through upregulating miR-122. HNF4G was a target of miR-122, and the effect of HNF4G on OS-732 cells was the same as HULC. Furthermore, overexpression of miR-122 inactivated PI3K/AKT, JAK/STAT, and Notch pathways by downregulation of HNF4G. These findings suggest that knockdown of HULC inhibited proliferation, migration, and invasion by sponging miR-122 in osteosarcoma cells. HULC may act as a novel therapeutic target for management of osteosarcoma.

High lncRNA HULC expression is associated with poor prognosis and promotes tumor progression by regulating epithelial-mesenchymal transition in prostate cancer.

IntroductionRecently, increasing evidence has shown that long non-coding RNAs (lncRNAs) play critical roles in tumor progression and development. However, the expression pattern and biological function of lncRNA HULC (highly upregulated in liver cancer) in prostate cancer (PCa) remain largely unclear.Material and methodsThe expression of lncRNA HULC in 53 paired PCa tissues and cell lines was detected by quantitative real-time polymerase chain reaction (qRT-PCR). The χ2 test was used to explore the association of lncRNA HULC expression with clinicopathologic features. Kaplan-Meier analysis was used to detect the association between HULC expression and overall survival of PCa patients. Furthermore, the function of HULC in cell growth and metastasis was detected in PCa cells.ResultsOur data showed that HULC expression was upregulated in PCa tissues and cell lines compared to adjacent non-tumor tissues and the normal prostate cell line RWPE-1 (p < 0.05). High HULC expression was positively associated with advanced clinicopathologic features and poor overall survival (OS) for PCa patients (p < 0.05). HULC inhibition suppressed PCa cell growth and metastasis both in vitro and in vivo (p < 0.05). Furthermore, HULC knockdown reduced N-cadherin and vimentin expression and increased E-cadherin expression in PCa cells (p < 0.05).ConclusionsOur data suggested that lncRNA HULC might play oncogenic roles in PCa progression, which provided a novel therapeutic strategy for PCa patients.