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Colorectal cancer (CRC) is still the third most common cancer in the world with a limited prognosis due to the chemoresistance of CRC cells to 5‐fluorouracil (5‐FU)‐based chemotherapy. In our previous study, we revealed that miR‐204 overexpression could sensitize CRC cell to 5‐FU treatment through targeting HMGA2/PI3K signaling pathway; however, miR‐204 expression in CRC tissues is abnormally downregulated. Long non‐coding RNAs (lncRNAs) dysregulation has been reported in human diseases, including cancer. Also, lncRNA can regulate cancer cell proliferation, invasion, migration, as well as chemoresistance. LncRNA prostate cancer‐associated transcript 6 (PCAT6) acts as an oncogene in many cancers; herein, PCAT6 expression was abnormally upregulated in CRC tissues and cell lines, suggesting its potential role in CRC. Further, we assessed the specific function and mechanism of PCAT6 in CRC. Furthermore, we revealed that PCAT6 knockdown attenuated CRC chemoresistance to 5‐FU through miR‐204/HMGA2/PI3K; miR‐204 inhibition could partially reverse the effect of PCAT6 knockdown. Taken together, we demonstrate that the abnormal PCAT6 overexpression inhibits miR‐204 expression in CRC, thereby promoting HMGA2/PI3K signaling activity, ultimately enhancing the chemoresistance of CRC cells to 5‐FU; PCAT6 represents a promising target for dealing with CRC chemoresistance. In the present study, we demonstrated that PCAT6 could modulate CRC chemoresistance to 5‐FU‐based chemotherapy through miR‐204/HMGA2/PI3K; PCAT6 represents a promising target for dealing with CRC chemoresistance.

Long noncoding RNA single nucleotide polymorphisms (lncRNA-SNPs) PCAT1 rs710886, PRNCR1 rs1456315 and CCAT2 rs6983267 on 8q24 region present generalizability in the susceptibility to multiple cancers, however, the influence of rs710886, rs1456315 and rs6983267 on lung cancer has not been assessed. The aim of this study was to investigate associations between three lncRNA-SNPs and lung cancer. A case-control study was performed on 438 patients with lung cancer and 456 healthy controls in the Han population from southern China. The collected samples were genotyped by the TaqMan genotyping, and the association with clinical characteristics, including age, gender, drinking status, smoking status, pathological types and clinical stages were analyzed. And the SNP function prediction was based on lncRNASNP2, RNAfold and GTEx. The rs1456315 T allele increased the risk of lung cancer [OR=1.95, 95% CI (1.58-2.43), =0.003] compared to the rs1456315 C allele, and rs1456315 significantly increased the risk of lung cancer in the dominant model [OR=1.86, 95% CI (1.16-3.00), =0.002]. The rs6983267 G allele, compared with the T allele, increased the risk of lung cancer [OR=1.29, 95% CI (1.07-1.57), =0.007], and rs6983267 was identified as a risk factor for lung cancer [OR=1.28, 95% CI (1.06-1.55), =0.003] in the additive model. Both rs1456315 and rs6983267 demonstrated significance after adjusting for the smoking status, drinking status and age. The structure prediction found rs6983267 and rs1456315 influence the secondary structure of its lncRNA. The results from lncRNASNP2 indicated that rs6983267 and rs1456315 change gain/loss target of miRNAs. rs1456315 and rs6983267 on 8q24 region are significantly associated with lung cancer in the Han population of southern China and alter the potential biological function in bioinformatic analysis, and the results further extended generalism of the susceptibility of cancer-associated lncRNA-SNPs to lung cancer and underlying mechanism involved in lung cancer.

Crucial parts of the genome including genes encoding microRNAs and noncoding RNAs went unnoticed for years, and even now, despite extensive annotation and assembly of the human genome, RNA‐sequencing continues to yield millions of unmappable and thus uncharacterized reads. Here, we examined > 300 billion reads from 536 normal donors and 1,873 patients encompassing 21 cancer types, identified ~300 million such uncharacterized reads, and using a distinctive approach de novo assembled 2,550 novel human transcripts, which mainly represent long noncoding RNAs. Of these, 230 exhibited relatively specific expression or non‐expression in certain cancer types, making them potential markers for those cancers, whereas 183 exhibited tissue specificity. Moreover, we used lentiviral‐mediated expression of three selected transcripts that had higher expression in normal than in cancer patients and found that each inhibited the growth of HepG2 cells. Our analysis provides a comprehensive and unbiased resource of unmapped human transcripts and reveals their associations with specific cancers, providing potentially important new genes for therapeutic targeting. Synopsis Comprehensive analysis of unmapped reads from a large number of cancer and normal RNA‐Seq datasets identifies 2,550 previously unassembled human transcripts. Some of the transcripts are cancer type‐ or tissue‐specific, suggesting context‐dependent functions. RNA‐sequencing reads that could not be mapped to the human reference genome/transcriptome are de novo assembled to obtain long and mainly noncoding transcripts. Alignment to chimp/gorilla genomes enabled predicting the genic neighborhood of these transcripts. Some transcripts associated with specific cancers/tissues are identified, and over‐expression of three selected transcripts is shown to affect the growth of HepG2 cells. Graphical Abstract Comprehensive analysis of unmapped reads from a large number of cancer and normal RNA‐Seq datasets identifies 2,550 previously unassembled human transcripts. Some of the transcripts are cancer type‐ or tissue‐specific, suggesting context‐dependent functions.

Long non-coding RNAs (lncRNAs) serve important roles in the tumorigenesis of a diverse range of cancer types. The lung cancer-associated transcript 1 (LUCAT1), has been reported to promote the proliferation, migration and invasion of oral squamous cell carcinoma cells. However, the exact role of LUCAT1 in laryngeal squamous cell carcinoma (LSCC) remains to fully understood. The present study aimed to interrogate the role and modulatory mechanism of LUCAT1 in LSCC. Reverse transcription-quantitative PCR and western blotting were used to investigate the expression of LUCAT1 and miR-493, as well as the protein expression of cyclin-dependent kinase 2, cyclin E1, p21, matrix metalloproteinase (MMP)2, MMP9, vascular endothelial growth factor-C, Bcl-2, Bax, cleaved caspase-3 and procaspase-3. Cell Counting Kit-8, flow cytometry, wound healing and Transwell assays were performed to analyze the proliferation, cell cycle, apoptosis levels, and the migratory and invasive abilities, respectively, of the LSCC AMC-HN-8 cell line. In addition, dual-luciferase reporter and ribonucleoprotein immunoprecipitation assays were used to investigate the binding between LUCAT1 and microRNA (miR)-493. The results of the present study revealed that the expression levels of LUCAT1 were upregulated in AMC-HN-8 cells. The genetic knockdown of LUCAT1 expression levels significantly suppressed the cell proliferation, alongside downregulating the expression levels of CDK2 and cyclin E1 and upregulating p21 expression levels. In addition, the knockdown of LUCAT1 inhibited cell migration and invasion, as demonstrated using the wound healing and Transwell assays, respectively. Moreover, LUCAT1 knockdown promoted cell apoptosis and upregulated the expression levels of Bax and cleaved caspase-3, whilst downregulating the expression levels of Bcl-2. Furthermore, LUCAT1 was discovered to directly bind to and inhibit the well-known tumor suppressor, miR-493. Notably, the specific inhibition of miR-493 partly blocked the anticancer effects of LUCAT1 knockdown in AMC-HN-8 cells. In conclusion, these results suggested that LUCAT1 may facilitate tumorigenesis in LSCC through the targeted inhibition of miR-493, which provides evidence for a novel target for the treatment of LSCC.

Colorectal cancer (CRC) is the third most commonly diagnosed cancer in both men and women in the USA. However, the underlying molecular mechanisms that drive CRC tumorigenesis are still not clear. Several studies have reported that long noncoding RNAs (lncRNAs) have important roles in tumor development. Here, we undertook a transcriptome microarray analysis in 6 pairs of CRC tissues and their corresponding adjacent normal tissues. A total of 1705 differentially expressed lncRNAs were detected in CRC tissues at stages I/II and III/IV (fold change greater than or equal to 2 or less than or equal to 0.5). Among them, we found that the lncRNA lung cancer‐associated transcript 1 (LUCAT1) was upregulated in CRC tissues and was closely associated with poor overall survival of CRC patients, through analysis of clinical data and The Cancer Genome Atlas. Functional studies indicated that LUCAT1 promoted CRC cell proliferation, apoptosis, migration, and invasion in vitro and in vivo. Furthermore, knockdown of LUCAT1 rendered CRC cells hypersensitive to oxaliplatin treatment. Mechanistically, bioinformatic analysis indicated that low expression of LUCAT1 was associated with the p53 signaling pathway. Chromatin isolation by RNA purification followed by mass spectrometry and RNA immunoprecipitation revealed that LUCAT1 bound with UBA52, which encodes ubiquitin and 60S ribosomal protein L40 (RPL40). We found that RPL40 functions in the ribosomal protein‐MDM2‐p53 pathway to regulate p53 expression. Taken together, our findings indicate that suppression of LUCAT1 induces CRC cell cycle arrest and apoptosis by binding UBA52 and activating the RPL40‐MDM2‐p53 pathway. These results implicate LUCAT1 as a potential prognostic biomarker and therapeutic target for CRC. Our study found that lung cancer associated transcript 1 (LUCAT1) was significantly increased in colorectal cancer (CRC) tissues and suppression of LUCTA1 induced CRC cell cycle arrest and apoptosis via binding UBA52 and activating the RPL40‐MDM2‐p53 pathway. Our data indicated that LUCAT1 is involved in CRC progression and may serve as a potential prognostic biomarker and a therapeutic target for CRC.

The long non-coding RNA colon cancer-associated transcript 2 (CCAT2) is abnormally expressed in various types of malignant tumor tissues and considered to be an oncogene, including for esophageal cancer (EC). Radiotherapy is an important and widely used cancer treatment. However, some patients with EC do not respond to radiotherapy. This study was designed to investigate effects of CCAT2 expression on radiotherapy dynamics for EC cells and to explore underlying molecular mechanisms. Reverse transcription-quantitative PCR was used to measure CCAT2 expression in EC tissues, normal esophageal mucosa, EC cells and normal human esophageal epithelial cells. TUNEL assays were used to assess the effect of CCAT2 on X-ray-induced apoptosis of EC cells. Protein expression was detected by western blot. CCAT2 was highly expressed in EC tissues and EC cells, and was negatively associated with radiotherapy efficacy in patients with EC. In vitro, knockdown of CCAT2 enhanced radiosensitivity of EC cells and promoted apoptosis by increasing Bax/Bcl2 and active-caspase 3/caspase 3 following X-ray treatment. In addition, CCAT2 negatively regulated miR-145 and P70 ribosomal protein S6 kinase 1 (p70S6K1) expression, and inhibited phosphorylation of Akt, ERK and p70S6K1 in EC cells. After X-ray treatment, CCAT2 negatively regulated protein levels of p53, P21 and c-Myc. These results showed that CCAT2 promoted the radiotherapy resistance of EC cells via negative regulation of the miR-145/p70S6K1 and the p53 signaling pathways and associated elements may be potential targets for improving the sensitivity of EC radiotherapy.

The aim of the present study was to determine the effect of the long non-coding RNA (lncRNA) bladder cancer-associated transcript 1 (BLACAT1) in chemoresistance of non-small cell lung cancer (NSCLC) cells. Expression of lncRNA BLACAT1, microRNA (miR)-17, autophagy-related protein 7 (ATG7), multidrug-resistance protein 1 (MRP1), and the autophagy-associated proteins light chain 3 (LC3)-II/LC3-I and Beclin 1 were detected using the reverse transcription-quantitative polymerase chain reaction and western blot analysis. Cell viability was determined using an MTT assay. The interaction between BLACAT1 and miR-17 was determined using RNA immunoprecipitation and RNA pull-down assays. A cisplatin (DDP)-resistant NSCLC cell A549/DDP xenograft model in nude mice was established to investigate the effect of BLACAT1 on the chemoresistance of NSCLC cells. Compared with in DDP-sensitive NSCLC cells, expression of BLACAT1, ATG7, MRP1, LC3-II/LC3-I and Beclin 1 was significantly upregulated in DDP-resistant NSCLC cells, whereas miR-17 was downregulated in DDP-resistant NSCLC cells. Short interfering RNA against BLACAT1 decreased the viability of DDP-resistant NSCLC cells. In addition, BLACAT1 interacted with miR-17, and negatively regulated miR-17. BLACAT1 promoted ATG7 expression through miR-17, and facilitated autophagy and promoted chemoresistance of NSCLC cells through miR-17/ATG7. Finally, in vivo experiments indicated that inhibition of BLACAT1 ameliorated the chemoresistance of NSCLC. BLACAT1 was upregulated in DDP-resistant NSCLC cells, and promoted autophagy and chemoresistance of NSCLC cells through the miR-17/ATG7 signaling pathway.

Ferroptosis, a recently discovered type of programmed cell death triggered by excessive accumulation of iron-dependent lipid peroxidation, is linked to several malignancies, including non-small cell lung cancer. Long non-coding RNAs (lncRNAs) are involved in ferroptosis; however, data on their role and mechanism in cancer therapy remains limited. Therefore, the aim of the present study was to identify ferroptosis-associated mRNAs and lncRNAs in A549 lung cancer cells treated with RAS-selective lethal 3 (RSL3) and ferrostatin-1 (Fer-1) using RNA sequencing. The results demonstrated that lncRNA lung cancer-associated transcript 1 (LUCAT1) was significantly upregulated in lung adenocarcinoma and lung squamous cell carcinoma tissues. Co-expression analysis of differentially expressed mRNAs and lncRNAs suggested that LUCAT1 has a crucial role in ferroptosis. LUCAT1 expression was markedly elevated in A549 cells treated with RSL3, which was prevented by co-incubation with Fer-1. Functionally, overexpression of LUCAT1 facilitated cell proliferation and reduced the occurrence of ferroptosis induced by RSL3 and Erastin, while inhibition of LUCAT1 expression reduced cell proliferation and increased ferroptosis. Mechanistically, downregulation of LUCAT1 resulted in the downregulation of both GTP cyclohydrolase 1 (GCH1) and ferroptosis suppressor protein 1 (FSP1). Furthermore, inhibition of LUCAT1 expression upregulated microRNA (miR)-34a-5p and then downregulated GCH1. These results indicated that inhibition of LUCAT1 expression promoted ferroptosis by modulating the downregulation of GCH1, mediated by miR-34a-5p. Therefore, the combination of knocking down LUCAT1 expression with ferroptosis inducers may be a promising strategy for lung cancer treatment.

Acquired epidermal growth factor receptor (EGFR) T790M mutation is the most common mechanism that accounts for EGFR-TKI (tyrosine kinase inhibitor) resistance of non-small cell lung cancer (NSCLC). High expense and acquired resistance weaken support for the use of osimertinib for T790M-positive NSCLC treatment, and limit the efficacy and application of this drug. Hyperoside, a flavonol glycoside compound, extracted from Hypericum perforatum, has been reported to inhibit the growth of a variety of tumors. The present study aimed to investigate the role of hyperoside in treating NSCLC with T790M mutations, and to elucidate the underlying molecular mechanisms. Cell viability assays, apoptosis analysis, reverse transcription-quantitative PCR, western blot analysis, animal experiments and immunohistochemistry were performed to examine the anticancer activity of hyperoside. Hyperoside inhibited the proliferation and induced the apoptosis of T790M-positive NSCLC cells. Hyperoside upregulated forkhead box protein O1 (FoxO1) expression and downregulated the level of long non-coding RNA (lncRNA) colon cancer associated transcript 1 (CCAT1) in T790M-positive NSCLC cells. In the in vivo study, hyperoside inhibited the growth of T790M-positive NSCLC xenografts. In conclusion, hyperoside inhibited proliferation and induced apoptosis by upregulating FoxO1 via CCAT1 in T790M-positive NSCLC both in vitro and in vivo, suggesting that hyperoside is a novel candidate for T790M-positive NSCLC treatment.

Osteosarcoma is a severe malignant tumor. Several studies indicated that lncRNA prostate cancer-associated transcript 6 (PCAT6) promoted the development of multiple types of cancers. Studies have also revealed that MDM2 could aggravate tumor symptoms inhibiting P53 expression. However, whether lncRNA PCAT6 could affect the proliferation and metastasis of osteosarcoma cells by regulating P53 expression is unclear. The present study established lncRNA PCAT6-overexpressing osteosarcoma cells. Cell Counting Kit-8, wound healing and Transwell assays were performed to detect the change in proliferation, migration and invasion of these cells, respectively. Subsequently, E3 ubiquitin-protein ligase Mdm2 (MDM2), P53 and P21 expression were determined using western blotting. Finally, MDM2 expression was inhibited and the proliferation, migration and invasion of these cells was determined again. The present study found that the proliferation, migration and invasion of osteosarcoma cells increased following overexpression of lncRNA PCAT6. MDM2 expression was upregulated while the levels of P53 and P21 decreased following overexpression of lncRNA PCAT6. However, the proliferation, migration and invasion of osteosarcoma cells were inhibited following MDM2 knockdown. Additionally, P53 and P21 was rescued following MDM2 knockdown. To conclude, lncRNA PCAT6 promoted the proliferation, migration and invasion of osteosarcoma cells by promoting the expression of MDM2 and suppressing the expression of P53 and P21.