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Background Gallbladder cancer is the most common biliary tract malignancy and not sensitive to chemotherapy. Autophagy is an important factor prolonging the survival of cancer cells under chemotherapeutic stress. We aimed to investigate the role of long non-coding RNAs (lncRNAs) in autophagy and chemoresistance of gallbladder cancer cells. Methods We established doxorubicin (Dox)-resistant gallbladder cancer cells and used microarray analysis to compare the expression profiles of lncRNAs in Dox-resistant gallbladder cancer cells and their parental cells. Knockdown or exogenous expression of lncRNA combined with in vitro and in vivo assays were performed to prove the functional significance of lncRNA. The effects of lncRNA on autophagy were assessed by stubRFP-sensGFP-LC3 and western blot. We used RNA pull-down and mass spectrometry analysis to identify the target proteins of lncRNA. Results The drug-resistant property of gallbladder cancer cells is related to their enhanced autophagic activity. And we found a lncRNA ENST00000425894 termed gallbladder cancer drug resistance-associated lncRNA1 (GBCDRlnc1) that serves as a critical regulator in gallbladder cancer chemoresistance. Furthermore, we discovered that GBCDRlnc1 is upregulated in gallbladder cancer tissues. Knockdown of GBCDRlnc1, via inhibiting autophagy at initial stage, enhanced the sensitivity of Dox-resistant gallbladder cancer cells to Dox in vitro and in vivo. Mechanically, we identified that GBCDRlnc1 interacts with phosphoglycerate kinase 1 and inhibits its ubiquitination in Dox-resistant gallbladder cancer cells, which leads to the down-regulation of autophagy initiator ATG5-ATG12 conjugate. Conclusions Our findings established that the chemoresistant driver GBCDRlnc1 might be a candidate therapeutic target for the treatment of advanced gallbladder cancer.

Background Though esophageal cancer is three to four times more common among males than females worldwide, this type of cancer still ranks in the top incidence among women, even more than the female specific cancer types. The occurrence is currently attributed to extrinsic factors, including tobacco use and alcohol consumption. However, limited attention has been given to gender-specific intrinsic genetic factors, especially in female. Methods We re-annotated a large cohort of microarrays on 179 ESCC patients and identified female-specific differently expressed lncRNAs. The associations between FMR1-AS1 and the risk and prognosis of ESCC were examined in 206 diagnosed patients from eastern China and validated in 188 additional patients from southern China. The effects of FMR1-AS1 on the malignant phenotypes on female ESCC cells were detected in vitro and in vivo. ChIRP-MS, reporter gene assays and EMSA were conducted to identify the interaction and regulation among FMR1-AS1 , TLR7 and NFκB. Results We found FMR1-AS1 expression is exclusively altered and closely associated with the level of sXCI in female ESCC patients, and its overexpression may correlate to poor clinical outcome. ChIRP-MS data indicate that FMR1-AS1 could be packaged into exosomes and released into tumor microenvironment. Functional studies demonstrated that FMR1-AS1 could bind to endosomal toll-like receptor 7 (TLR7) and activate downstream TLR7-NFκB signaling, promoting the c-Myc expression, thus inducing ESCC cell proliferation, anti-apoptosis and invasion ability. Exosome incubation and co-xenograft assay indicate that FMR1-AS1 exosomes may secreted from ESCC CSCs, transferring stemness phenotypes to recipient non-CSCs in tumor microenvironment. Furthermore, we also found a correlation between the serum levels of FMR1-AS1 and the overall survival (OS) of the female ESCC patients. Conclusions Our results highlighted exosomal FMR1-AS1 in maintaining CSC dynamic interconversion state through the mechanism of activating TLR7-NFκB signaling, upregulating c-Myc level in recipient cells, which may be taken as an attractive target approach for advancing current precision cancer therapeutics in female patients.

Background Chemoresistance to cisplatin (DDP) remains a major challenge in advanced gastric cancer (GC) treatment. Although accumulating evidence suggests an association between dysregulation of long non‐coding RNAs (lncRNAs) and chemoresistance, the regulatory functions and complexities of lncRNAs in modulating DDP‐based chemotherapy in GC remain under‐investigated. This study was designed to explore the critical chemoresistance‐related lncRNAs in GC and identify novel therapeutic targets for patients with chemoresistant GC. Methods Chemoresistance‐related lncRNAs were identified through microarray and verified through a quantitative real‐time polymerase chain reaction (qRT‐PCR). Proteins bound by lncRNAs were identified through a human proteome array and validated through RNA immunoprecipitation (RIP) and RNA pull‐down assays. Co‐immunoprecipitation and ubiquitination assays were performed to explore the molecular mechanisms of the Musashi2 (MSI2) post‐modification. The effects of LINC00942 (LNC942) and MSI2 on DDP‐based chemotherapy were investigated through MTS, apoptosis assays and xenograft tumour formation in vivo. Results LNC942 was found to be up‐regulated in chemoresistant GC cells, and its high expression was positively correlated with the poor prognosis of patients with GC. Functional studies indicated that LNC942 confers chemoresistance to GC cells by impairing apoptosis and inducing stemness. Mechanically, LNC942 up‐regulated the MSI2 expression by preventing its interaction with SCFβ‐TRCP E3 ubiquitin ligase, eventually inhibiting ubiquitination. Then, LNC942 stabilized c‐Myc mRNA in an N6‐methyladenosine (m6A)‐dependent manner. As a potential m6A recognition protein, MSI2 stabilized c‐Myc mRNA with m6A modifications. Moreover, inhibition of the LNC942‐MSI2‐c‐Myc axis was found to restore chemosensitivity both in vitro and in vivo. Conclusions These results uncover a chemoresistant accelerating function of LNC942 in GC, and disrupting the LNC942‐MSI2‐c‐Myc axis could be a novel therapeutic strategy for GC patients undergoing chemoresistance. 1. LNC942 is a vital chemoresistant‐related lncRNA in gastric cancer. 2. LNC942 prevents β‐Trcp‐mediated MSI2 degradation. Then, MSI2 recognizes and stabilizes the c‐Myc mRNA in an m6A‐dependent manner. 3. Treatment with MSI2 inhibitor FK228 could overcome LNC942‐induced cisplatin resistance in gastric cancer.

Pulmonary arterial hypertension (PAH) is related to inflammation, and the lncRNA H19 is associated with inflammation. However, whether PDGF-BB-H19-let-7b-AT R axis contributes to the pathogenesis of PAH has not been thoroughly elucidated to date. This study investigated the role of H19 in PAH and its related mechanism. In the present study, SD rats, C57/BL6 mice and H19-/- mice were injected with monocrotaline (MCT) to establish a PAH model. H19 was detected in the cytokine-stimulated pulmonary arterial smooth muscle cells (PASMCs), serum and lungs of rats/mice. H19 overexpression and knockdown experiments were also conducted. A dual luciferase reporter assay was used to explore whether let-7b is a sponge miRNA of H19, and AT R is a novel target of let-7b. A CCK-8 assay and flow cytometry were used to analyse cell proliferation. The results showed that H19 was highly expressed in the serum and lungs of MCT-induced rats/mice, and H19 was upregulated by PDGF-BB in vitro. H19 upregulated AT R expression via sponging miRNA let-7b following PDGF-BB stimulation. AT R is a novel target of let-7b. Moreover, the overexpression of H19 and AT R could facilitate PASMCs proliferation in vitro. H19 knockout protected mice from pulmonary artery remodeling and PAH following MCT treatment. Our study showed that H19 is highly expressed in MCT-induced rodent lungs and upregulated by PDGF-BB. The H19-let-7b-AT R axis contributed to the pathogenesis of PAH by stimulating PASMCs proliferation. The H19 knockout had a protective role in the development of PAH. H19 may be a potential tar-get for the treatment of PAH.

Nucleophosmin ( NPM1 ) is the most commonly mutated gene in acute myeloid leukemia (AML) resulting in aberrant cytoplasmic translocation of the encoded nucleolar protein (NPM1c + ). NPM1c + maintains a unique leukemic gene expression program, characterized by activation of HOXA / B clusters and MEIS1 oncogene to facilitate leukemogenesis. However, the mechanisms by which NPM1c + controls such gene expression patterns to promote leukemogenesis remain largely unknown. Here, we show that the activation of HOXBLINC , a HOXB locus-associated long non-coding RNA (lncRNA), is a critical downstream mediator of NPM1c + -associated leukemic transcription program and leukemogenesis. HOXBLINC loss attenuates NPM1c + -driven leukemogenesis by rectifying the signature of NPM1c + leukemic transcription programs. Furthermore, overexpression of HoxBlinc ( HoxBlinc Tg) in mice enhances HSC self-renewal and expands myelopoiesis, leading to the development of AML-like disease, reminiscent of the phenotypes seen in the Npm1 mutant knock-in ( Npm1 c/+ ) mice. HoxBlinc Tg and Npm1 c/+ HSPCs share significantly overlapped transcriptome and chromatin structure. Mechanistically, HoxBlinc binds to the promoter regions of NPM1c + signature genes to control their activation in HoxBlinc Tg HSPCs, via MLL1 recruitment and promoter H3K4me3 modification. Our study reveals that HOXBLINC lncRNA activation plays an essential oncogenic role in NPM1c + leukemia . HOXBLINC and its partner MLL1 are potential therapeutic targets for NPM1c + AML. Nucleophosmin (NPM1) gene mutation induces a specific gene expression program leading to acute myeloid leukaemia. Here, the authors show that mutant NPM1 activates a HOXB locus-associated long non-coding RNA which is essential for its associated oncogenic transcriptional program and leukaemia development.

Background Long noncoding RNAs (lncRNAs), defined as the transcripts longer than 200 nt without protein-coding capacity, have been found to be aberrantly expressed in diverse human diseases including cancer. A reciprocal translocation between chromosome 9 and 22 generates the chimeric Bcr-Abl oncogene, which is associated with several hematological malignancies. However, the functional relevance between aberrantly expressed lncRNAs and Bcr-Abl-mediated leukemia remains obscure. Methods LncRNA cDNA microarray was used to identify novel lncRNAs involved in Bcr-Abl-mediated cellular transformation. To study the functional relevance of novel imatinib-upregulated lncRNA (IUR) family in Abl-induced tumorigenesis, Abl-transformed cell survival and xenografted tumor growth in mice was evaluated. Primary bone marrow transformation and in vivo leukemia transplant using lncRNA-IUR knockdown (KD) transgenic mice were further conducted to corroborate the role of lncRNA-IUR in Abl-induced tumorigenesis. Transcriptome RNA-seq, Western blot, RNA pull down and RNA Immunoprecipitation (RIP) were employed to determine the mechanisms by which lncRNA-IUR-5 regulates Bcr-Abl-mediated tumorigenesis. Results We identified a conserved lncRNA-IUR family as a key negative regulator of Bcr-Abl-induced tumorigenesis. Increased expression of lncRNA-IUR was detected in both human and mouse Abl-transformed cells upon imatinib treatment. In contrast, reduced expression of lncRNA-IUR was observed in the peripheral blood lymphocytes derived from Bcr-Abl-positive acute lymphoblastic leukemia (ALL) patients compared to normal subjects. Knockdown of lncRNA-IUR remarkably promoted Abl-transformed leukemic cell survival and xenografted tumor growth in mice, whereas overexpression of lncRNA-IUR had opposite effects. Also, silencing murine lncRNA-IUR promoted Bcr-Abl-mediated primary bone marrow transformation and Abl-transformed leukemia cell survival in vivo. Besides, knockdown of murine lncRNA-IUR in transgenic mice provided a favorable microenvironment for development of Abl-mediated leukemia. Finally, we demonstrated that lncRNA-IUR-5 suppressed Bcr-Abl-mediated tumorigenesis by negatively regulating STAT5-mediated expression of CD71. Conclusions The results suggest that lncRNA-IUR may act as a critical tumor suppressor in Bcr-Abl-mediated tumorigenesis by suppressing the STAT5-CD71 pathway. This study provides new insights into functional involvement of lncRNAs in leukemogenesis.

Understanding the underlying mechanisms of pediatric osteosarcoma (OS) migration and invasion is important for prognosis and treatment. We tried to measure the expression of long non-coding RNA HLA complex group 18 (HCG18) in OS and reveal its function in the malignant behaviors of OS cells. This study detected the expression of HCG18, miR-188-5p and forkhead box C1 (FOXC1) in OS tissues and cell lines by quantitative real-time PCR (qRT-PCR). The relevance between miR-188-5p and HCG18 or FOXC1 was affirmed by dual-luciferase reporter (DLR) assay. Cell viability was analyzed by MTT assay. Transwell assay was utilized to test cell invasion and migration. FOXC1 protein expression was detected by western blot. HCG18 expression was elevated in OS tissues, and enhanced HCG18 expression was related to metastasis. HCG18 silencing repressed the viability, migration and invasion of OS cells. Moreover, HCG18 interacted with miR-188-5p. MiR-188-5p up-regulation repressed cell viability, invasion and migration in OS cells. FOXC1, a known target of miR-188-5p, was negatively modulated by miR-188-5p. Furthermore, miR-188-5p inhibition or FOXC1 over-expression partially abolished the reduced of cell viability, invasion and migration mediated by HCG18 silencing in OS cell lines. This study revealed that HCG18 knockdown repressed the viability, invasion and migration of OS cells by targeting miR-188-5p and regulating FOXC1 expression. Thus, HCG18/ miR-188-5p/FOX may be a hopeful target for OS therapy.

The aim of the present study was to determine the competitive endogenous RNA (ceRNA) network associated with long-coding RNA (lncRNA) LA16c-313D11.11 in endometrial cancer (EC). Initially, the expression levels of LA16c-313D11.11 in 60 EC tissues, 20 atypical hyperplasia endometrium (EAH) tissues and 20 normal endometrium tissues was determined. MicroRNA (miRNA/miR)-205-5p mimics and LA16c-313D11.11 mimics were transfected into HEC-1A and Ishikawa cells. The expression levels of miR-205-5p, LA16c-313D11.11 and their target proteins were assessed using reverse transcription-quantitative PCR or western blot analysis. Flow cytometry, Cell Counting kit-8 assays, Transwell migration assays and wound healing assays were performed to assess the effects of LA16c-313D11.11 and miR-205-5p on the migration and proliferation of tumor cells in vitro. The expression levels of LA16c-313D11.11 and phosphatase and tensin homolog deleted on chromosome ten (PTEN) in human EAH and EC tissues were significantly decreased, whereas the expression levels of miR-205-5p in EAH and EC tissues were significantly increased, compared with the normal endometrium tissues. The expression of LA16c-313D11.11 in human EC tissues negatively correlated with the expression of miR-205-5p. Additionally, the overexpression of LA16c-313D11.11 significantly reduced the invasion, migration and viability of HEC-1A and Ishikawa cells in vitro. LA16c-313D11.11 was shown to regulate the expression of PTEN, and the invasion, migration and viability of HEC-1A and Ishikawa cells, through its microRNA response element to compete for microRNA-205-5p. LA16c-313D11.11 was also shown to modulate the PI3K/AKT signaling pathway. Therefore, LA16c-313D11.11 acts as an effective ceRNA associated with a microRNA-205-5p-PTEN axis. LA16c-313D11.11 may inhibit the development and progression of EC by acting as a sponge of miR-205-5p, thus indirectly increasing the expression of PTEN.

The long-term chronic inflammation of cervical intraepithelial neoplasia (CIN) induces the initiation and progression of cervical cancer. Long non-coding RNAs (LncRNAs) are being identified to be involved into inflammation and carcinogenesis and could function as cancer biomarkers in clinical. However, the significance of inflammation-related LncRNA (e.g. LncRNA-IL7R) in cervical cancer is limited. We, here, investigated the clinical role of inflammation-related LncRNA-IL7R (Lnc-IL7R) in healthy cervical tissue (n=15), CIN 1/2/3 (n=35), cervical cancer (n=70), and clarified its function via knockdown in vitro and in vivo. The results showed that the expression of Lnc-IL7R was increased from normal tissues to neoplastic lesions and cervical cancer. Up-regulated Lnc-IL7R positively correlated to tumor size, International Federation of Gynaecology and Obstetrics (FIGO) stage, and lymph node metastasis (LNM). Patients with high expression of Lnc-IL7R had poor prognosis with short overall survival (OS) time, and Cox regression analysis revealed that Lnc-IL7R could be independent prognostic factor for cervical cancer. Moreover, knockdown of Lnc-IL7R by two different siRNAs in cervical cancer cell lines Hela and SiHa induced impaired cell vitality and caspase-3-dependent apoptosis in vitro. Furthermore, inhibition of Lnc-IL7R in vivo significantly restricted the tumor growth with decreased expressions of proliferation index Ki-67 and Lnc-IL7R. These data indicated that Lnc-IL7R predicts a poor clinical outcome of cervical cancer patients, and knockdown of Lnc-IL7R is amenable to the treatment of cervical cancer.

We previously performed long non-coding RNA (lncRNA) expression microarray analyses to identify novel indicators for gastric cancer (GC) metastasis and prognosis in which we identified lncRNA XLOC_010235 (XLOC) as a candidate RNA. However, XLOC_010235 molecular mechanism of action remains unclear. Gain and loss of function approaches were used to investigate the biological role of XLOC in vitro . The effects of XLOC on cell viability were assessed by CCK-8 proliferation assays. Real-time PCR, western-blot and immunofluorescence were used to evaluate the mRNA and protein expression of Snail and multiple EMT related molecules. The positive XLOC/Snail1 interaction was identified and verified by immunohistochemistry assay and bivariate correlation analysis. Ectopic expression of XLOC facilitate cell viability, migration and invasion, leading to the acceleration of metastasis, while depletion of XLOC expression hindered cell migration and invasion. Moreover, over-expression of XLOC was found to play a important role in epithelial-to-mesenchymal transition (EMT) through the regulation of E-cadherin, N-cadherin and Vimentin expression, in which transcriptional factor Snail1 was involved. These results advance our understanding of the role of lncRNA XLOC_010235 as a active regulator of EMT by associating with Snail1, which may help in the development of new therapeutics.