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Neuropathic pain is a severe and debilitating condition caused by damage to the peripheral nerve or central nervous system. Although several mechanisms have been identified, the underlying pathophysiology of neuropathic pain is still not fully understood. Unfortunately, few effective therapies are available for this condition. Therefore, there is an urgent need to investigate the underlying mechanisms of neuropathic pain to develop more effective treatments. Long non-coding RNAs (lncRNAs) have recently gained attention due to their potential to modulate protein expression through various mechanisms. LncRNAs have been implicated in many diseases, including neuropathic pain. This study aimed to identify a novel lncRNA involved in neuropathic pain progression. The lncRNA microarray analysis showed that lncRNA Upregulated in Liver Cancer (HULC) was significantly upregulated in spinal cord tissue of sciatic nerve injury (SNI) rats. Further experiments confirmed that HULC promoted neuropathic pain progression and aggravated H2O2-induced Schwann cell injury. Mechanistically, Sine Oculis Homeobox 1 (SIX1) regulated the transcriptional expression of HULC, and both SIX1 and HULC were involved in neuropathic pain and Schwann cell injury. The results of our research indicate the existence of a previously unknown SIX1/HULC axis that plays a significant role in the development and progression of neuropathic pain, shedding light on the complex mechanisms that underlie this debilitating condition. These findings offer novel insights into the molecular pathways involved in neuropathic pain. This study underscores the potential of targeting lncRNAs as a viable approach to alleviate the suffering of patients with neuropathic pain.

Dysregulation of microRNAs (miRNAs or miRs) is implicated in the development of gastric cancer (GC), which is possibly related to their roles in targeting tumor-suppressive or tumor-promoting genes. Herein, the current study was intended to ascertain the function of miR-488 and its modulatory mechanism in GC. Initially, human GC cells were assayed for their in vitro malignancy after miRNA gain- or loss-of-function and RNA interference or overexpression. Also, tumorigenesis and liver metastasis were evaluated in nude mouse models. Results demonstrated that miR-488 elevation suppressed GC (MKN-45 and OCUM-1) cell proliferation, migration, and invasiveness in vitro and reduced their tumorigenesis and liver metastasis in vivo. The luciferase assay identified that miR-488 bound to HULC and inhibited its expression. Furthermore, HULC could enhance EZH2-H3K27me3 enrichment at the p53 promoter region and epigenetically repress the p53 expression based on the data from RIP- and ChIP-qPCR assay. Additionally, HULC was validated to enhance GC growth and metastasis in vitro and in vivo. Overall, HULC re-expression elicited by miR-488 inhibition can enhance EZH2-H3K27me3 enrichment in the p53 promoter and repress the p53 expression, thus promoting the growth and metastasis of GC.

Insulin-like growth factor I receptor (IGF1R) is frequently upregulated in breast cancer. Due to its intrinsic tyrosine kinase activity, aberrant activation of the IGF1R signaling axis may enhance tumor cell proliferation and cancer stemness, causing tumor relapse, metastasis and resistance to chemotherapy. We utilized a chromatin RNA in situ reverse transcription (CRIST) approach to characterize molecular factors that regulate the IGF1R network. We identified lncRNA HULC (Highly Upregulated in Liver Cancer) as a key trans-regulator of IGF1R in breast cancer cells. Loss of HULC suppressed the expression of IGF1R and the activation of its downstream PI3K/AKT pathway, while HULC overexpression activated the axis in breast cancer cells. Using a transcription-associated trap (RAT) assay, we demonstrated that HULC functioned as a nuclear lncRNA and epigenetically activated IGF1R by directly binding to the intragenic regulatory elements of the gene, orchestrating intrachromosomal interactions, and promoting histone H3K9 acetylation. The activated HULC-IGF1R/PI3K/AKT pathway mediated tumor resistance to cisplatin through the increased expression of cancer stemness markers, including NANOG, SOX2, OCT4, CD44 and ALDH1A1. In immunodeficient mice, stimulation of the HULC-IGF1R pathway promoted tumor metastasis. These data suggest that HULC may be a new epigenetic target for IGF1R axis-targeted therapeutic intervention.

Acute myocardial infarction (AMI) is a ubiquitous cardiovascular disease ensuing adverse prognosis caused by myocardial necrosis. Effective and rapid diagnosis of AMI is essential to following treatment in clinical practice while the existed biomarkers have inherent limitations. Consequently, exploration of novel biomarkers is needed. Long noncoding RNA (lncRNA) emerges as the upcoming biomarkers adopted in clinical use, and we aim at investigating the diagnostic power of lncRNA TTTY15 and HULC in AMI patients.
We measured lncRNA level in 80 AMI patients and 36 healthy volunteers in discovering cohort and 50 AMI patients and 20 healthy volunteers in verification cohort with quantitative RT-PCR method. Receiver operating characteristic (ROC) analysis was administered to detect the diagnostic power of selected lncRNAs. Regression and correlation analyses were performed to explore the related factors.
ROC analysis reveals the superiority of TTTY15 and HULC as biomarkers against conventional AMI biomarkers CKMB (AUC of TTTY15: 0.915 versus CKMB: 0.768 versus TnT: 0.869); AUC of HULC: 0.905 versus CKMB: 0.768 versus TnT: 0.869). Regression and correlation analysis indicates that TTTY15 and HULC may be one of the contributing factors to AMI and related to accepted risk factors.
Our results revealed the diagnostic potency of lncRNA TTTY15 and HULC, and they could also be treated as novel therapeutic targets in AMI therapy, hinting inspiration to the cardiologist in clinical practice.

This meta-analysis aimed to evaluate the correlation between lncRNA HULC, prognosis and clinicopathological characteristics in patients with digestive system tumors.
The relevant literatures were collected through PubMed, Web of Science and Embase up to February 2021. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to assess the prognostic value of HULC in patients with digestive system tumors. The clinicopathological characteristics of HULC in patients were estimated by odds ratios (ORs).
A total of 14 studies involving 1312 patients were included. The up-regulated expression level of HULC was associated with poorer overall survival (OS) in patients with digestive system tumors (HR = 1.83, 95% CI: 1.05-3.19, P = 0.033). Subgroup analysis showed that cancer type (pancreatic cancer or gastric cancer), residence region (China, Japan or Korea), and specimen (serum) significantly associated between HULC and OS. In addition, high HULC expression significantly increased the risk of high TNM stage (OR = 2.51, 95%CI: 1.36-4.62, P < 0.05), poor differentiation (OR = 1.38, 95%CI: 1.02-1.87, P < 0.05) and lymphatic node metastasis (LNM, OR = 4.93, 95% CI: 3.47-6.99, P < 0.05).
High expression level of HULC is related to OS, TNM stage, differentiation and LNM. Therefore, HULC can be used as a new potential predictor for prognosis and clinicopathological features of patients with digestive system tumors.

In recent years, several case-control studies have explored the association between the rs7763881 locus polymorphism of the HULC gene and cancer risk, however, the findings have been inconsistent. Therefore, a meta-analysis was conducted to clarify the association. Relevant case-control studies were obtained from CNKI, Embase, Web of Science and PubMed databases. RevMan software was used to perform data analysis. A total of 8 case-control studies containing 4036 cases and 5286 controls were included in the current meta-analysis. The overall analysis results showed no significant association between the rs7763881 locus polymorphism and cancer risk. However, stratified analysis based on cancer type showed that the rs7763881 locus polymorphism was associated with the decreased risk of hepatocellular cancer, colorectal cancer and esophageal cancer. In conclusion, the current findings suggest that the rs7763881 polymorphic loci located on the HULC gene may serve as a biomarker for determining an individual\'s risk of hepatocellular cancer, colorectal cancer and esophageal cancer.

Highly upregulated in liver cancer (HULC) had a significant predictive effect on tumor growth and metastasis of hepatocellular carcinoma (HCC); however, the mechanisms of HULC on HCC still need to be clarified. We attempted to determine the roles of HULC and miR-107 in autophagy and invasion of HCC. HULC siRNA reduced the level of autophagy. The impact of HULC siRNA on invasion can be reversed by activating autophagy in HCC cell lines. Further studies on HULC and autophagy were conducted. An interacting sequence between HULC and miR-107, as well as miR-107 and Atg12, was predicted by software. The relationship of each pair of molecules was confirmed by luciferase reporter assays. The negative impacts of miR-107 on autophagy and invasion were proved in HCC cell lines. The inhibitor of miR-107-promoted invasion can also be reversed by Atg12 siRNA. The changes of miR-107, Atg12, epithelial-mesenchymal transition, and autophagy in transplanted tumors of mouse models also confirmed the results in HCC cell lines. Finally, we find that HULC acts as an endogenous sponge, which abolishes the binding of miR-107 on the Atg12 3\'-UTR and promotes autophagy and metastasis of HCC.

We aimed to explore the function and underlying mechanism of highly upregulated in liver cancer (HULC; an long noncoding RNAs) in hepatocellular carcinoma (HCC) and chemosensitivity of oxaliplatin (Oxa). The expression of HULC, miR-383-5p, and vesicle-associated membrane protein-2 (VAMP2) was detected by quantitative real-time polymerase chain reaction. Western blot assay was applied for measuring the protein expression of cyclinD1, cleaved-caspase-3, light Chain 3 I/II, p62, and VAMP2. Cell viability and Oxa IC50 value were determined by Cell Counting Kit-8 assay. A colony formation assay was conducted to evaluate colony formation ability. Cell apoptosis was assessed by flow cytometry. The interaction between miR-383-5p and HULC or VAMP2 was predicted by bioinformatics analysis and verified by dual-luciferase reporter assay and RNA immunoprecipitation assay. The mice xenograft model was established to investigate the roles of HULC in vivo. HULC and VAMP2 were overexpressed whereas miR-383-5p was lowly expressed in HCC tissues. HULC overexpression promoted the progression of HCC cells and inhibited chemosensitivity of Oxa by increasing cell proliferation and protective autophagy and inhibiting apoptosis, whereas HULC silence presented opposite effects. Moreover, miR-383-5p was a direct target of HULC and miR-383-5p reversed the effects of HULC on the progression of HCC cells and chemosensitivity of Oxa. Besides, HULC acted as a molecular sponge of miR-383-5p to regulate VAMP2 expression. HULC promoted the progression of HCC and inhibited Oxa sensitivity by regulating miR-383-5p/VAMP2 axis, elucidating a novel regulatory mechanism for chemosensitivity of Oxa and providing a potential lncRNA-targeted therapy for HCC.

OBJECTIVE: The study aims to elucidate the impact of LncRNA HULC in human skin fibroblasts (HSF) after burns in children. HULC might act as endogenous sponges for miR-663b to regulate the gene expression of TLR4.
METHODS: This study included 46 children with deep second-degree burns. On the 5th day after the injury, eligible samples from all patients were collected. HSF cells were selected to establish a thermal-injured model. qRT-PCR was applied to detect the expression of HULC, miR-663b, and TLR4 mRNA in burn wound and normal skin tissue. The dual-luciferase reporter and RIP assay were performed to explore a targeted binding relationship between HULC and miR-663b, or miR-663b and TLR4. Cell proliferation and invasion were evaluated through the assay of CCK-8 and transwell assay. The expression levels of α-SMA, Collagen I, MMP-1, and TIMP-1, which are associated with extracellular matrix (ECM) production, were examinated by western blot.
RESULTS: HULC and TLR4 mRNA expression were reduced on the 5th day after thermal injury in burn wounds, while miR-663b expression increased significantly (P<0.05), when compared to expression in the normal tissue. HULC and TLR4 mRNA concentration in HSF cells showed a transient increase after thermal injury, and a gradual decline with time was observed subsequently when compared to the control group. An inverse expression of miR-663b with the expression of HULC and TLR4 mRNA was observed simultaneously (P<0.05). A deficiency of HULC promotes the proliferation, invasion, and ECM synthesis of HSF cells with thermal injury; HULC functions as a ceRNA of miR-663b. Inhibitors of miR-663b partially rescued the effects on thermal-injured HSF cells induced by HULC deficiency (P<0.05). TLR4 is a target gene of miR-663b. The up-regulation of TLR4 also partially reversed the effect on the thermal-injury of HSF cells resulting from HULC deficiency (P<0.05).
CONCLUSIONS: LncRNA HULC may function as a molecular sponge to regulate the expression of the miR-663b/TLR4, and thereby inhibit the proliferation, invasion, and ECM synthesis of thermal-injured HSF cells. HULC knockdown might significantly promote wound healing in children after burns.