BACKGROUND: One of the confounding factors in pancreatic cancer (PC) pathogenesis is hyperglycemia. The molecular mechanism by which high glucose (HG) influences PC severity is poorly understood. Our investigation delved into the impact of lncRNA highly upregulated in liver cancer (HULC) and its interaction with yes-associated protein (YAP) in regulating the fate of pancreatic ductal adenocarcinoma cells (PDAC) under HG-induced conditions. PDAC cells were cultured under normal or HG conditions. We thereafter measured the effect of HG on the viability of PDAC cells, their migration potential and drug resistance properties. The lncRNAs putatively dysregulated in PC and diabetes were shortlisted by bioinformatics analysis followed by wet lab validation of function.
RESULTS: HG led to enhanced proliferation and drug refractoriness in PDAC cells. HULC was identified as one of the major deregulated lncRNAs following bioinformatics analysis. HULC was found to regulate the expression of the potent transcriptional regulator - YAP through selective histone modifications at the YAP promoter. siRNA-mediated ablation of HULC resulted in a concurrent decrease in YAP transcriptional activity. Importantly, HULC and YAP were found to co-operatively regulate the cellular homeostatic process autophagy, thus inculcating drug resistance and proliferative potential in PDAC cells. Moreover, inhibition of autophagy or YAP led to a decrease in HULC levels, suggesting the existence of an inter-regulatory feedback loop.
CONCLUSIONS: We observed that HG triggers aggressive properties in PDAC cells. Mechanistically, up-regulation of lncRNA HULC resulted in activation of YAP and differential regulation of autophagy coupled to increased proliferation of PDAC cells.
CONCLUSIONS: Inhibition of HULC and YAP may represent a novel therapeutic strategy for PDAC. Furthermore, this study portrays the intricate molecular interplay between HULC, YAP and autophagy in PDAC pathogenesis.

Long noncoding RNAs (lncRNAs) are RNA molecules of 200 nucleotides or more in length that are not translated into proteins. Their expression is tissue-specific, with the vast majority involved in the regulation of cellular processes and functions. Many human diseases, including cancer, have been shown to be associated with deregulated lncRNAs, rendering them potential therapeutic targets and biomarkers for differential diagnosis. The expression of lncRNAs in the nervous system varies in different cell types, implicated in mechanisms of neurons and glia, with effects on the development and functioning of the brain. Reports have also shown a link between changes in lncRNA molecules and the etiopathogenesis of brain neoplasia, including glioblastoma multiforme (GBM). GBM is an aggressive variant of brain cancer with an unfavourable prognosis and a median survival of 14-16 months. It is considered a brain-specific disease with the highly invasive malignant cells spreading throughout the neural tissue, impeding the complete resection, and leading to post-surgery recurrences, which are the prime cause of mortality. The early diagnosis of GBM could improve the treatment and extend survival, with the lncRNA profiling of biological fluids promising the detection of neoplastic changes at their initial stages and more effective therapeutic interventions. This review presents a systematic overview of GBM-associated deregulation of lncRNAs with a focus on lncRNA fingerprints in patients\' blood.

BACKGROUND: Highly upregulated in liver cancer (HULC) is one of the LncRNAs that was documented to enhance cancer progression, and its downregulation is associated with cell cycle arrest and apoptosis. Myotubularin-related protein 3 (MTMR3) is required for autophagy, and many studies consider MTMR3 to be a negative regulator of autophagy processes. However, nothing is understood about how they regulate breast cancer.
METHODS: This case-control study included 245 patients (Group A: 85 early BC Group B: 40 metastatic BC cases, Group C: 40 fibroadenoma cases; and Group D: 80 age matched healthy control subjects. TaqMan Real-time PCR was used to analyse rs7158663 and rs12537. MTMR3 and HULC gene expression levels were measured using RT-PCR.
RESULTS: Breast cancer patients exhibited elevated serum MTMR3 and HULC compared to fibroadenomas and control cases. The MTMR3 rs12537 \"T/T\" genotype was highly expressed in cases of breast cancer (early and metastatic) compared to controls (risk genotype). On the other hand, the HULC rs7158663 genotypes were not statistically associated with breast cancer. However, when compared to the control, the C/C genotype of the HULC gene is higher in the case.MTMR3 gene expression was higher in the T/T genotype compared to both the C/C and C/T genotypes, while HULC gene expression was lower in the A/C genotype compared to both the A/A and C/C genotypes. Positive correlation between MTMR3 and HULC. MTMR3 and ALT, as well as HULC and alkaline phosphatase, both showed a statistically significant positive correlation.
CONCLUSIONS: Our findings reveal that MTMR3 and HULC serum expression and their SNPs (HULC rs7763881, MTMR3 rs12537) are associated with a higher risk for the development of breast cancer in the Egyptian population.

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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.

Hepatocellular carcinoma (HCC) is a highly prevalent malignancy. It is a common type of cancer in Egypt due to chronic virus C infection (HCV). Currently, the frequently used lab test is serum α-fetoprotein. However, its diagnostic value is challenging due to its low sensitivity and specificity. Genetic biomarkers have recently provided new insights for cancer diagnostics. Herein, we quantified Lnc HULC and miR-122 gene expression to test their potential in diagnosis. Both biomarkers were tested in the sera of 60 HCC patients and 60 with chronic HCV using real-time RT-PCR. miR-122 was highly expressed in HCV patients with a significant difference from the HCC group (p = 0.004), which points towards its role in prognosis value as a predictor of HCC in patients with chronic HCV. HULC was more highly expressed in HCC patients than in the HCV group (p = 0.018), indicating its potential use in screening and the early diagnosis of HCC. The receiver operating characteristic (ROC) curve analysis showed their reliable sensitivity and specificity. Our results reveal that miR-122 can act as a prognostic tool for patients with chronic HCV. Furthermore, it is an early predictor of HCC. LncRNA HULC can be used as an early diagnostic tool for HCC.

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.