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An insufficient oxygen supply within the intratumoral environment, also known as hypoxia, induces glioblastoma multiforme (GBM) invasion, stemness, and temozolomide (TMZ) drug resistance. Long noncoding (lnc)RNAs have been reported to be involved in hypoxia and GBM progression. However, their roles in hypoxic GBM malignancy are still unclear. We investigated the mechanisms of hypoxia‐mediated lncRNAs in regulating GBM processes. Using The Cancer Genome Atlas (TCGA) and data mining, hypoxia‐correlated lncRNAs were identified. A hypoxia‐upregulated lncRNA, MIR210HG, locating in nuclear regions, predicted poor prognoses of patients and modulated hypoxia‐promoted glioma stemness, TMZ resistance, and invasion. Depletion of hypoxic MIR210HG suppressed GBM and patient‐derived cell growth and increased TMZ sensitivity in vitro and vivo. Using RNA sequencing and gene set enrichment analysis (GSEA), MIR210HG‐upregulated genes significantly belonged to the targets of octamer transcription factor 1 (OCT1) transcription factor. The direct interaction between OCT1 and MIR210HG was also validated. Two well‐established worse prognostic factors of GBM, insulin‐like growth factor–binding protein 2 (IGFBP2) and fibroblast growth factor receptor 1 (FGFR1), were identified as downstream targets of OCT1 through MIR210HG mediation in hypoxia. Consequently, the lncRNA MIR210HG is upregulated by hypoxia and interacts with OCT1 for modulating hypoxic GBM, leading to poor prognoses. These findings might provide a better understanding in functions of hypoxia/MIR210HG signaling for regulating GBM malignancy. Hypoxia‐inducible lncRNA MIR210HG predicts a poor prognosis in hypoxic glioblastoma multiforme (GBM) malignancy. MIR210HG directly interacts with OCT1 in hypoxic GBM malignancy. MIR210HG upregulates IGFBP2 and FGFR1 through OCT1 in hypoxic GBM malignancy.

Background Long noncoding (lnc)RNAs and glycolysis are both recognized as key regulators of cancers. Some lncRNAs are also reportedly involved in regulating glycolysis metabolism. However, glycolysis-associated lncRNA signatures and their clinical relevance in cancers remain unclear. We investigated the roles of glycolysis-associated lncRNAs in cancers. Methods Glycolysis scores and glycolysis-associated lncRNA signatures were established using a single-sample gene set enrichment analysis (GSEA) of The Cancer Genome Atlas pan-cancer data. Consensus clustering assays and genomic classifiers were used to stratify patient subtypes and for validation. Fisher’s exact test was performed to investigate genomic mutations and molecular subtypes. A differentially expressed gene analysis, with GSEA, transcription factor (TF) activity scoring, cellular distributions, and immune cell infiltration, was conducted to explore the functions of glycolysis-associated lncRNAs. Results Glycolysis-associated lncRNA signatures across 33 cancer types were generated and used to stratify patients into distinct clusters. Patients in cluster 3 had high glycolysis scores and poor survival, especially in bladder carcinoma, low-grade gliomas, mesotheliomas, pancreatic adenocarcinomas, and uveal melanomas. The clinical significance of lncRNA-defined groups was validated using external datasets and genomic classifiers. Gene mutations, molecular subtypes associated with poor prognoses, TFs, oncogenic signaling such as the epithelial-to-mesenchymal transition (EMT), and high immune cell infiltration demonstrated significant associations with cluster 3 patients. Furthermore, five lncRNAs, namely MIR4435-2HG, AC078846.1, AL157392.3, AP001273.1, and RAD51-AS1, exhibited significant correlations with glycolysis across the five cancers. Except MIR4435-2HG, the lncRNAs were distributed in nuclei. MIR4435-2HG was connected to glycolysis, EMT, and immune infiltrations in cancers. Conclusions We identified a subgroup of cancer patients stratified by glycolysis-associated lncRNAs with poor prognoses, high immune infiltration, and EMT activation, thus providing new directions for cancer therapy.

Temozolomide (TMZ) is a first-line alkylating agent for glioblastoma multiforme (GBM). Clarifying the mechanisms inducing TMZ insensitivity may be helpful in improving its therapeutic effectiveness against GBM. Insulin-like growth factor (IGF)-1 signaling and micro (mi)RNAs are relevant in mediating GBM progression. However, their roles in desensitizing GBM cells to TMZ are still unclear. We aimed to identify IGF-1-mediated miRNA regulatory networks that elicit TMZ insensitivity for GBM. IGF-1 treatment attenuated TMZ cytotoxicity via WNT/β-catenin signaling, but did not influence glioma cell growth. By miRNA array analyses, 93 upregulated and 148 downregulated miRNAs were identified in IGF-1-treated glioma cells. miR-513a-5p from the miR-513a-2 gene locus was upregulated by IGF-1-mediated phosphoinositide 3-kinase (PI3K) signaling. Its elevated levels were also observed in gliomas versus normal cells, in array data of The Cancer Genome Atlas (TCGA), and the GSE61710, GSE37366, and GSE41032 datasets. In addition, lower levels of neural precursor cell-expressed developmentally downregulated 4-like (NEDD4L), an E3 ubiquitin protein ligase that inhibits WNT signaling, were found in gliomas by analyzing cells, arrays, and RNA sequencing data of TCGA glioma patients. Furthermore, a negative correlation was identified between miR-513a-5p and NEDD4L in glioma. NEDD4L was also validated as a direct target gene of miR-513a-5p, and it was reduced by IGF-1 treatment. Overexpression of NEDD4L inhibited glioma cell viability and reversed IGF-1-repressed TMZ cytotoxicity. In contrast, miR-513a-5p significantly affected NEDD4L-inhibited WNT signaling and reduced TMZ cytotoxicity. These findings demonstrate a distinct role of IGF-1 signaling through miR-513a-5p-inhibited NEDD4L networks in influencing GBM's drug sensitivity to TMZ.

Monoamine oxidase B (MAOB), a neurotransmitter‐degrading enzyme, was reported to reveal conflicting roles in various cancers. However, the functional role of MAOB and impacts of its genetic variants on prostate cancer (PCa) is unknown. Herein, we genotyped four loci of MAOB single‐nucleotide polymorphisms (SNPs), including rs1799836 (A/G), rs3027452 (G/A), rs6651806 (A/C) and rs6324 (G/A) in 702 PCa Taiwanese patients. We discovered that PCa patients carrying the MAOB rs6324 A‐allele exhibited an increased risk of having a high initial prostate‐specific antigen (iPSA) level (>10 ng/mL). Additionally, patients with the rs3027452 A‐allele had a higher risk of developing distal metastasis, particularly in the subpopulation with high iPSA levels. In a subpopulation without postoperative biochemical recurrence, patients carrying the rs1799836 G‐allele had a higher risk of developing lymph node metastasis and recurrence compared to those carrying the A‐allele. Furthermore, genotype screening in PCa cell lines revealed that cells carrying the rs1799836 G‐allele expressed lower MAOB levels than those carrying the A‐allele. Functionally, overexpression and knockdown of MAOB in PCa cells respectively suppressed and enhanced cell motility and proliferation. In clinical observations, correlations of lower MAOB expression levels with higher Gleason scores, advanced clinical T stages, tumour metastasis, and poorer prognosis in PCa patients were noted. Our findings suggest that MAOB may act as a suppressor of PCa progression, and the rs3027452 and rs1799836 genetic variants of MAOB are linked to PCa metastasis within the Taiwanese population.

DNA damage-inducible transcript 4 (DDIT4) is known to participate in various cancers, including glioblastoma multiforme (GBM). However, contradictory roles of DDIT4 exist in inducing cell death and possessing anti-apoptotic functions against cancer progression. Herein, we investigated DDIT4 signaling in GBM and temozolomide (TMZ) drug resistance. We identified that TMZ induced DDIT4 upregulation, leading to desensitization against TMZ cytotoxicity in GBM cells. Higher DDIT4 levels were found in glioma cells and mesenchymal-type GBM patients, and these higher levels were positively correlated with mesenchymal markers. Furthermore, patients with lower DDIT4 levels, especially O-6-methylguanine-DNA methyltransferase (MGMT)-methylated patients, exhibited better TMZ therapeutic efficacy. We determined that higher levels of 5 DDIT4-associated downstream genes, including SLC2A3 (also known as glucose transporter 3 (GLUT3)), can be used to predict a poor prognosis. Among these 5 genes, only GLUT3 was upregulated in both TMZ-treated and DDIT4-overexpressing cells. DDIT4-mediated GLUT3 expression was also identified, and its expression decreased TMZ's cytotoxicity. A significant correlation existed between DDIT4 and GLUT3. DDIT4 signaling was found to be involved in both glycolytic and autophagic pathways. However, GLUT3 only participated in the exhibition of DDIT4-mediated stemness, resulting from glycolytic regulation, but not in DDIT4-mediated autophagic signaling. Finally, we identified TMZ-upregulated activating transcription factor 4 (ATF4) as an upstream regulator of DDIT4-mediated GLUT3/stemness signaling and autophagy. Consequently, ATF4/DDIT4 signaling was connected to both autophagy and GLUT3-regulated stemness, which are involved in TMZ drug resistance and the poor prognoses of GBM patients. Targeting DDIT4/GLUT3 signaling might be a new direction for glioma therapy.

CD26/dipeptidyl peptidase IV (DPP4) is a multifunctional cell‐surface glycoprotein widely found in many cell types, and a soluble form is present in body fluids. There is longstanding evidence indicating a tumour‐promoting or ‐suppressive role of DPP4 in different cancer types. However, studies focusing on the impacts of genetic variants of DPP4 on cancers are very rare. Herein, we conducted a case–control study to evaluate whether single‐nucleotide polymorphisms (SNPs) of DPP4 were associated with the risk or clinicopathologic development of prostate cancer (PCa). We genotyped four loci of DPP4 SNPs, including rs7608798 (A/G), rs3788979 (C/T), rs2268889 (T/C) and rs6741949 (G/C), using a TaqMan allelic discrimination assay in 704 PCa patients and 704 healthy controls. Our results showed that PCa patients with the DPP4 rs7608798 AG+GG genotype or rs2268889 TC+CC genotype had a higher risk of developing an advanced clinical primary tumour (cT) stage (adjusted odds ratio (AOR): 1.680, 95% confidence interval (CI): 1.062–2.659, p = 0.025; AOR: 1.693, 95% CI: 1.092–2.624, p = 0.018). Additionally, in The Cancer Genome Atlas (TCGA) database, we observed that lower DPP4 expression levels were correlated with higher Gleason scores, advanced cT and pathological stages, tumour metastasis, and shorter progression‐free survival rates in PCa patients. Furthermore, overexpression of DPP4 suppressed migration/invasion of metastatic PC3 PCa cells. Our findings suggest that DPP4 levels may affect the progression of PCa, and the DPP4 rs7608798 and rs2268889 SNPs are associated with the clinicopathologic development of PCa in a Taiwanese population.

Chitinase 3‐like 1 (CHI3L1 or YKL40) is a secreted glycoprotein highly expressed in advanced stages of several cancer types, including prostate cancer (PCa). Impacts of genetic variants of CHI3L1 on PCa development have not yet been investigated. The most common well‐studied genetic variations are single‐nucleotide polymorphisms (SNPs). Therefore, the objective of this study was to explore associations of CHI3L1 SNPs with both the susceptibility to PCa and its clinicopathological development. Three promoter SNPs, rs6691378 (−1371, G>A), rs10399805 (−247, G>A) and rs4950928 (−131, C>G), and one non‐synonymous SNP, rs880633 (+2950, T>C), were analysed using a TaqMan allelic discrimination assay for genotyping in a cohort of 701 PCa patients and 701 healthy controls. Results indicated that there were no significant associations of PCa susceptibility with these four CHI3L1 SNPs. However, among elderly PCa patients (aged >65 years), it was observed that polymorphic variants (GA + AA) of CHI3L1 rs6691378 and 10399805 were significantly linked to reduced risks of several clinicopathological characteristics, including a high Gleason grade, advanced pathologic T stage and tumour cell invasion. Moreover, analyses of The Cancer Genome Atlas database revealed that CHI3L1 expression levels were elevated in PCa tissues compared with normal tissues. Interestingly, higher CHI3L1 expression levels were found to be associated with longer progression‐free survival rates in PCa patients. Our findings indicated that levels of CHI3L1 may influence the progression of PCa, and the rs6691378 and 10399805 SNP genetic variants of CHI3L1 are linked to the clinicopathological development of PCa within a Taiwanese population.

Temozolomide (TMZ), an alkylating agent of the imidazotetrazine series, is a first-line chemotherapeutic drug used in the clinical therapy of glioblastoma multiforme, the most common and high-grade primary glioma in adults. Micro (mi)RNAs, which are small noncoding RNAs, post-transcriptionally regulate gene expressions and are involved in gliomagenesis. However, no studies have reported relationships between TMZ and miRNA gene regulation. We investigated TMZ-mediated miRNA profiles and its molecular mechanisms underlying the induction of glioma cell death. By performing miRNA microarray and bioinformatics analyses, we observed that expression of 248 miRNAs was altered, including five significantly upregulated and 17 significantly downregulated miRNAs, in TMZ-treated U87MG cells. miR-128 expression levels were lower in different glioma cells and strongly associated with poor survival. TMZ treatment significantly upregulated miR-128 expression. TMZ significantly enhanced miR-128-1 promoter activity and transcriptionally regulated miR-128 levels through c-Jun N-terminal kinase 2/c-Jun pathways. The overexpression and knockdown of miR-128 expression significantly affected TMZ-mediated cell viability and apoptosis-related protein expression. Furthermore, the overexpression of miR-128 alone enhanced apoptotic death of glioma cells through caspase-3/9 activation, poly(ADP ribose) polymerase degradation, reactive oxygen species generation, mitochondrial membrane potential loss, and non-protective autophagy formation. Finally, we identified that key members in mammalian target of rapamycin (mTOR) signaling including mTOR, rapamycin-insensitive companion of mTOR, insulin-like growth factor 1, and PIK3R1, but not PDK1, were direct target genes of miR-128. TMZ inhibited mTOR signaling through miR-128 regulation. These results indicate that miR-128-inhibited mTOR signaling is involved in TMZ-mediated cytotoxicity. Our findings may provide a better understanding of cytotoxic mechanisms of TMZ involved in glioblastoma development.

The most susceptible loci of hepatocellular carcinoma (HCC) identified by genome‐wide association studies are located in non‐coding regions. The antisense non‐coding RNA at the INK4 locus (ANRIL), also known as cyclin‐dependent kinase inhibitor 2B antisense RNA 1 (CDKN2B‐AS1), is a long non‐coding (lnc)RNA situated within and antisense to genes encoding CDKN2A/B on chromosome 9p21.3. Single‐nucleotide polymorphisms (SNPs) within CDKN2B‐AS1 are associated with several cancer types, but their impacts on HCC remain unclear. In this study, we investigated the effects of CDKN2B‐AS1 SNPs on both the susceptibility to HCC and its clinicopathological development. Five CDKN2B‐AS1 SNP loci—rs564398 (T/C), rs1333048 (A/C), rs1537373 (G/T), rs2151280 (A/G) and rs8181047 (G/A)—were analysed using a TaqMan allelic discrimination assay for genotyping in a cohort of 810 HCC patients and 1190 healthy controls. Under the dominant model, HCC patients with at least one minor C‐allele of rs564398 showed a lower risk of liver cirrhosis (odds ratio (OR) = 0.677). Additionally, HCC patients with the GT + TT genotype of rs1537373 had a reduced risk of developing large tumours (T3 + T4) and advanced clinical stages (III/IV), particularly in the male population (OR = 0.644 and 0.679). Furthermore, data from The Cancer Genome Atlas revealed that CDKN2B‐AS1 expression levels were elevated in HCC tissues compared to normal tissues and were correlated with advanced T stages, high histological grades and poor prognoses. Our findings suggest that CDKN2B‐AS1 levels and its polymorphic variants at rs564398 and rs1537373 may influence the clinicopathological development and progression of HCC in a Taiwanese population.

Background KH-type splicing regulatory protein (KHSRP, also called KSRP), a versatile RNA-binding protein, plays a critical role in various physiological and pathological conditions through modulating gene expressions at multiple levels. However, the role of KSRP in clear cell renal cell carcinoma (ccRCC) remains poorly understood. Methods KSRP expression was detected by a ccRCC tissue microarray and evaluated by an in silico analysis. Cell loss-of-function and gain-of-function, colony-formation, anoikis, and transwell assays, and an orthotopic bioluminescent xenograft model were conducted to determine the functional role of KRSP in ccRCC progression. Micro (mi)RNA and complementary (c)DNA microarrays were used to identify downstream targets of KSRP. Western blotting, quantitative real-time polymerase chain reaction, and promoter- and 3-untranslated region (3'UTR)-luciferase reporter assays were employed to validate the underlying mechanisms of KSRP which aggravate progression of ccRCC. Results Our results showed that dysregulated high levels of KSRP were correlated with advanced clinical stages, larger tumor sizes, recurrence, and poor prognoses of ccRCC. Neural precursor cell-expressed developmentally downregulated 4 like (NEDD4L) was identified as a novel target of KSRP, which can reverse the protumorigenic and prometastatic characteristics as well as epithelial-mesenchymal transition (EMT) promotion by KSRP in vitro and in vivo. Molecular studies revealed that KSRP can decrease NEDD4L messenger (m)RNA stability via inducing mir-629-5p upregulation and directly targeting the AU-rich elements (AREs) of the 3’UTR. Moreover, KSRP was shown to transcriptionally suppress NEDD4L via inducing the transcriptional repressor, Wilm's tumor 1 (WT1). In the clinic, ccRCC samples revealed a positive correlation between KSRP and mesenchymal-related genes, and patients expressing high KSRP and low NEDD4L had the worst prognoses. Conclusion The current findings unveil novel mechanisms of KSRP which promote malignant progression of ccRCC through transcriptional inhibition and post-transcriptional destabilization of NEDD4L transcripts. Targeting KSRP and its pathways may be a novel pharmaceutical intervention for ccRCC.