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Abstract: Cancer is one of the compelling and pegged diseases battled by clinicians and researchers worldwide. Among different types of cancer, oral cancer holds the sixth position globally. With an escalating prevalence in Asian countries, India, China, and Pakistan constitute a large proportion of total incidents of oral cancer patients in terms of new cases or deaths. This mounting prevalence is ascribed to poor oral hygiene and rampant use of substances earmarked as potential risk factors for the disease. Risk factors (dietary/lifestyle habits/occupational/environmental) trigger the activation of oncogenes, dysregulation of lncRNA and miRNA, and silence the tumor suppressor genes, which robustly contributes to the onset and progression of tumorigenesis in oral squamous cell carcinoma. Evidence suggests that specific carcinogens identified in tobacco and related products alter many cellular pathways predisposing to advanced stages of oral cancer. Long non-coding RNAs represent a broad group of heterogenous transcripts longer than 200 nucleotides which do not translate to form functional proteins. They regulate various cellular pathways by specifically interacting with other RNAs, DNA, and proteins. Their role in the pathogenesis of OSCC and other cancer is still being debated. In this review, we discuss the molecular insights of significant lncRNAs involved in some crucial deregulated pathways of tobacco-associated OSCC. The implications and challenges to harnessing the potential of lncRNAs as biomarkers in early diagnosis and targeted treatment have also been analyzed.

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous and aggressive tumor with high mortality and unfavorable prognosis. Numerous long non-coding RNAs (lncRNAs) have been confirmed to exert pivotal parts in cancers. Nevertheless, the functions of most lncRNAs in HNSCC need deeper exploration. Our present research tried to clarify the biological role of TM4SF19 antisense RNA 1 (TM4SF19-AS1) and investigate its regulatory mechanism in HNSCC. RT-qPCR analysis was done to test TM4SF19-AS1 expression and identify the up-regulation of TM4SF19-AS1 in HNSCC cells. Loss-of-function assays were also involved, and the data implied that TM4SF19-AS1 knockdown hampered the proliferation, migration, invasion, along with epithelial-mesenchymal transition (EMT) of HNSCC cells. In vivo assays revealed TM4SF19-AS1 depletion restrained HNSCC tumor growth. Additionally, mechanism experiments were implemented to uncover the underlying regulatory mechanism of TM4SF19-AS1 in HNSCC cells. It turned out that TM4SF19-AS1 modulated laminin subunit gamma 1 (LAMC1) expression via sequestering microRNA-153-3p (miR-153-3p) and recruiting heterogeneous nuclear ribonucleoprotein C (HNRNPC) protein. Rescue assays confirmed that TM4SF19-AS1 contributed to HNSCC cell malignant behaviors via up-regulating LAMC1. To summarize, TM4SF19-AS1 played an oncogenic role in HNSCC cells, signifying TM4SF19-AS1 may have the potential to be used as a novel molecular target for HNSCC diagnosis.

Emerging evidence shows that the lncRNA THOR is deeply involved in the development of various cancers. However, the effects and underlying molecular mechanisms of THOR in breast cancer (BRCA) initiation and progression have not been fully elucidated. Here we show that THOR is critical for BRCA tumorigenesis by interacting with hnRNPD to regulate downstream signaling pathways. THOR expression was significantly higher in BRCA tissues than in normal tissues, and THOR upregulation was associated with a poor prognosis in BRCA patients. Functionally, THOR knockdown impaired cell proliferation, migration and invasion in BRCA cells in vitro and inhibited tumorigenesis and metastasis in a tumor xenograft model and THOR-deficient MMTV-PyMT model in vivo. Mechanistically, THOR bound to the hnRNPD protein and increased hnRNPD protein levels by maintaining hnRNPD protein stability through inhibition of the proteasome-dependent degradation pathway. The increased hnRNPD protein levels led to stabilization of its target mRNAs, including pyruvate dehydrogenase kinase 1 (PDK1), further activating downstream PI3K-AKT and MAPK signaling pathways to regulate BRCA cell proliferation and metastasis. Together, our findings indicate that THOR is a promising prognostic predictor for BRCA patients and that the THOR-hnRNPD-PDK1-MAPK/PI3K-AKT axis might be a potential therapeutic target for BRCA treatment.

Background: Endometrial cancer (EC) is an intractable gynecological cancer with increasing incidence and mortality worldwide. Accumulating studies indicated that long noncoding RNA nuclear enriched...

Background: Angiogenesis is a hallmark of cancer, which is regulated by diverse factors, including long non-coding RNAs (lncRNAS). Our previous study showed that the long non-coding RNA H22954 inhibits tumor growth, albeit whether it is involved in the angiogenesis of cancer re-mains unknown. Objectives: This study aimed to investigate the role of lncRNA H22954 in angiogenesis of acute myeloid leukemia (AML) and the underlying molecular mechanism. Methods: Bioinformatics analysis was conducted to screen the targeted molecule of H22954. Western blot and ELISA analysis detected PDGFA protein expression, and RT-qPCR detected H22954 and PDGFA expression in cell lines and AML samples. Dual-luciferase reporter gene assay and half-life assay were applied to validate the relationship between H22954 and PDGFA. The functional experi-ment was conducted to investigate the role of H22954 in tube formation. Results: Overexpression of H22954 inhibited angiogenesis in mouse xenograft tumors and cultured acute myeloid leukemia (AML) cells. Bioinformatics analysis and luciferase assay revealed that H22954 targeted the 3’ untranslated region (UTR) of the platelet-derived growth factor subunit A (PDGFA) gene. In transfected cells, H22954 overexpression reduced PDGFA expression and protein levels. Tube formation was rescued following the addition of exogenous human PDGFA to the con-ditioned medium from cells overexpressing H22954. The expression of H22954 in K562 cells re-duced the half-life of PDGFA mRNA. Furthermore, H22954 expression was inversely correlated with PDGFA expression in patient samples. Conclusion: These findings indicate that H22954 inhibits angiogenesis in AML through the down-regulation of PDGFA expression. Administering recombinant lncRNA H22954 may be a therapeutic approach for patients with AML.

c-Myc and E2F1 play critical roles in many human cancers. As long noncoding RNAs (lncRNA) are known to regulate various tumorigenic processes, elucidation of mechanisms of cross-talk between lncRNAs and c-Myc/E2F1-related signaling pathways could provide important insights into cancer biology. In this study, we used integrated bioinformatic analyses and found that the lncRNA MNX1-AS1 is upregulated in non–small cell lung cancer (NSCLC) via copy-number gain and c-Myc–mediated transcriptional activation. High levels of MNX1-AS1 were associated with poor clinical outcomes in patients with lung cancer. MNX1-AS1 promoted cell proliferation and colony formation in vitro and tumor growth in vivo. MNX1-AS1 bound and drove phase separation of IGF2BP1, which increased the interaction of IGF2BP1 with the 3′-UTR (untranslated region) of c-Myc and E2F1 mRNA to promote their stability. The c-Myc/MNX1-AS1/IGF2BP1 positive feedback loop accelerated cell-cycle progression and promoted continuous proliferation of lung cancer cells. In a lung cancer patient-derived xenograft model, inhibition of MNX1-AS1 suppressed cancer cell proliferation and tumor growth. These findings offer new insights into the regulation and function of c-Myc and E2F1 signaling in NSCLC tumorigenesis and suggest that the MNX1-AS1/IGF2BP1 axis may serve as a potential biomarker and therapeutic target in NSCLC. Significance: MNX1-AS1 drives phase separation of IGF2BP1 to increase c-Myc and E2F1 signaling and to activate cell-cycle progression to promote proliferation in NSCLC.

Melanoma is a kind of aggressive skin neoplasms with high mortality. The purpose of this present research was to investigate the effects and potential mechanisms of long-noncoding RNA (lncRNA) MSC antisense RNA 1 (MSC-AS1) in melanoma. MSC-AS1, miR-330-3p and YAP1 expression levels in melanoma tissues and cells were assessed by quantitative real-time polymerase chain reaction. Melanoma cells were evaluated using cell count kit-8, clone formation and ELISA in vitro . The relationship among MSC-AS1, YAP1 and miR-330-3p was validated by pull-down and luciferase reporter assays. Finally, the role of MSC-AS1 in vivo was determined by the xenograft model. Results showed that lncRNA MSC-AS1 was upregulated in melanoma tissues and cells. High expression of MAS-AS1 was positively correlated with a poor prognosis. Pull-down and luciferase reporter demonstrated that miR-330-3p specifically binds directly to YAP1 and MSC-AS1, respectively. MSC-AS1 promoted the expression of YAP1 by downregulating miR-330-3p. Functional experiments suggested that knockdown of MSC-AS1 suppressed the proliferation of melanoma cells and decreased the levels of glutamine, glutamate and α-ketoglutarate, glutaminase and glutamine transporter alanine-serine-cysteine transporter 2. Upregulation of miR-330-3p alleviated the promotion effect of MSC-AS1 overexpression on the proliferation and glutaminolysis of melanoma cells. The above changes could be reversed by YAP1 overexpression. In addition, knockdown of MSC-AS1 dramatically restrained the growth of melanoma cells in xenograft model. In conclusion, our results revealed that MSC-AS1 facilitated the proliferation and glutaminolysis of melanoma cells by regulating miR-330-3p/ YAP1 pathway, suggesting that MSC-AS1 could provide a new idea for the treatment of melanoma.

Background: Breast cancer is one of the most prevalent cancers that often occur in females. Long noncoding RNA differentiation antagonizing nonprotein coding RNA (DANCR) has been involved in the pathogenesis of various tumors, including breast cancer. This study aimed to investigate the role and underlying mechanism of DANCR in breast cancer. Materials and Methods: The level of DANCR was detected in breast cancer tissues and cells by quantitative real-time polymerase chain reaction (qRT-PCR). Cell viability was evaluated by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assay. Cell apoptosis was assessed using flow cytometry. Cell migration and invasion were estimated by the Transwell assay. The relationship between DANCR, miR-4319, and vesicle-associated membrane protein-associated protein B (VAPB) was confirmed by bioinformatic analysis and dual-luciferase reporter assay. The level of microRNA-4319 (miR-4319) was tested by qRT-PCR. The expression of VAPB was measured by qRT-PCR or western blot assay. Results: DANCR and VAPB were upregulated, while miR-4319 was downregulated in breast cancer tissues and cells. Knockdown of DANCR hindered proliferation, migration, and invasion and promoted apoptosis of breast cancer cells. DANCR knockdown inhibited breast cancer development through regulating miR-4319. Inhibition of miR-4319 restrained breast cancer cell progression by targeting VAPB. Moreover, DANCR regulated VAPB expression by sponging miR-4319 in breast cancer cells. Conclusion: DANCR facilitated breast cancer cell progression through regulating the miR-4319/VAPB axis, indicating that DANCR might be a potential biomarker and therapeutic target for breast cancer treatment.

To determine if long-chain non-coding RNA (lncRNA) MIR4435-2HG (MIR4435) expression is associated with pre-malignant colon polyps and colon cancer.Children's colonic-polyp specimens were sequenced for MIR4435 expression. LncRNA MIR4435 expression data in colorectal cancer and normal intestinal tissues were retrieved from The Cancer Genome Atlas (TCGA). The proliferation, adhesion, and invasion ability of human colon-cancer cell line HCT116 with or without MIR4435 knockdown was analyzed. The expression of Smad4, desmoplakin, and β-catenin genes was detected by western blotting in HCT116 cells.MIR4435 expression correlated with the size of intestinal polyps in children. Expression of MIR4435 was up-regulated in colorectal cancer. MIR4435 knockdown in HCT116 cells inhibited their proliferation, adhesion, and invasion ability. Smad4 and desmoplakin were up-regulated and β-catenin was down-regulated in HCT116 cells by MIR4435 knockdown.MIR4435 expression correlated with the size of intestinal polyps in children and with the proliferation, adhesion, and invasion ability of colon-cancer cells and was upregulated in colon cancer.

The view of long noncoding RNAs as nonfunctional "garbage" has been definitely outdated by the large body of evidence indicating this class of ncRNAs as "golden junk", especially in precision oncology. Indeed, in light of their oncogenic role and the higher expression in multiple cancer types compared with paired adjacent tissues, the clinical interest for lncRNAs as diagnostic and/or prognostic biomarkers has been rapidly increasing. The emergence of large-scale sequencing technologies, their subsequent diffusion even in small research and clinical centers, the technological advances for the detection of low-copy lncRNAs in body fluids, coupled to the huge reduction of operating costs, have nowadays made possible to rapidly and comprehensively profile them in multiple tumors and large cohorts. In this review, we first summarize some relevant data about the oncogenic role of well-studied lncRNAs having a clinical relevance. Then, we focus on the description of their potential use as diagnostic/prognostic biomarkers, including an updated overview about licensed patents or clinical trials on lncRNAs in oncology.

Background. Colorectal cancer is one of the most common gastrointestinal malignancies globally. Necroptosis has been proved to play a role in the occurrence and development of the tumor, which makes it a new target for molecular therapy. However, the role of necroptosis in colorectal cancer remains unknown yet. Our study aims to build a prognostic signature of necroptosis-related lncRNAs (nrlncRNAs) to predict the outcomes of patients with colorectal cancer and facilitate in anticancer therapy. Method. We obtained RNA-seq and clinical data of colorectal adenocarcinoma from the TCGA database and got prognosis-related nrlncRNAs by univariate regression analysis. Then, we carried out the LASSO regression and multivariate regression analysis to build the prognostic signature, whose predictive ability was tested by the Kaplan-Meier as well as ROC curves and verified by the internal cohort. Moreover, we divided the cohort into 2 groups based on median of risk scores: high- and low-risk groups. By analyzing the difference in the tumor microenvironment, microsatellite instability, and tumor mutation burden between the two groups, we explored the potential chemotherapy and immunotherapy drugs. Results. We screened out 9 nrlncRNAs and built a prognostic signature based on them. With its good prognostic ability, the risk scores can act as an independent prognostic factor for patients with colorectal cancer. The overall survival rate of patients in high-risk group was significantly higher than the low-risk one. Furthermore, risk scores can also give us hints about the tumor microenvironment and facilitate in predicting the response to the CTLA-4 blocker treatment and other chemotherapeutic agents with potential efficacy such as cisplatin and staurosporine. Conclusions. In conclusion, our prognostic signature of necroptosis-related lncRNAs can facilitate in predicting the prognosis and response to the anticancer therapy of colorectal cancer patients.

Abnormal translation of the MYC proto-oncogene is a hallmark of the initiation and maintenance of tumorigenesis. However, the molecular mechanism underlying increased MYC protein levels in certain cancer types without a corresponding increase in MYC mRNA levels is unclear. Here, we identified a novel lncRNA, MTAR1, which is critical for post-transcriptional regulation of MYC-induced tumorigenesis. MTAR1 is essential for recruiting IGF2BPs into PABP1-mediated liquid-liquid phase separation (LLPS) complexes and facilitates IGF2BPs-mediated MYC mRNA translation. MTAR1 enhanced binding between IGF2BPs and PABP1, thereby promoting MYC mRNA stability and increased MYC mRNA translation. In summary, MTAR1 is a novel MYC-related lncRNA that contributes to tumor progression by enhancing MYC translation through mediating PABP1/IGF2BPs liquid-liquid phase separation.

Background Long non-coding RNA (lncRNA) exhibits a crucial role in multiple human malignancies. The expression of lncRNA LINC00511, reportedly, is aberrantly up-regulated in several types of tumors. Our research was aimed at deciphering the role and mechanism of LINC00511 in the progression of cervical cancer (CC). Method Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to quantify the expression levels of LINC00511, miR-497-5p and MAPK1 mRNA in CC tissues and cell lines. Cell counting kit-8 (CCK-8), 5-bromo-2’-deoxyuridine (BrdU) and Transwell assays were conducted for detecting the proliferation, migration and invasion of CC cells. Dual-luciferase reporter gene experiments were performed to verify the targeting relationships amongst LINC00511, miR-497-5p and MAPK1. Besides, MAPK1 expression in CC cells was detected via Western blot after LINC00511 and miR-497-5p were selectively regulated. Results Up-regulation of LINC00511 expression in CC tissues and cell lines was observed, which was in association with tumor size, clinical stage and lymph node metastasis of the patients. LINC00511 overexpression facilitated the proliferation, migration and invasion of CC cells, while opposite effects were observed after knockdown of LINC00511. Mechanistically, LINC00511 was capable of targeting miR-497-5p and up-regulating MAPK1 expression. Conclusion LINC00511/miR-497-5p/MAPK1 axis regulates CC progression.

Accumulating evidence suggests that lncRNAs are potential biomarkers and key regulators of tumor development and progression. However, the precise function of most lncRNAs in glioma remains unknown. In this study, we explored the role of long intergenic non-protein coding RNA 1018 (LINC01018) in human glioma.Expression levels of LINC01018 and miR-182-5p in clinical glioma tissues and cell lines were detected by quantitative real-time PCR (qRT-PCR). Cell proliferation, migration, and invasion were determined by Cell Counting Kit-8 (CCK-8) assay and Transwell assay. Epithelial-mesenchymal transition (EMT) related proteins were measured by Western blotting. Direct relationship between LINC01018 and miR-182-5p was tested by dual-luciferase reporter assay, RNA immunoprecipitation assay (RIP), and rescue assays. Lastly, bioinformatics analyses were conducted to predict the downstream factors of LINC01018/miR-182-5p axis in glioma.LINC01018 was significantly down-regulated in glioma tissues and cell lines. Overexpression of LINC01018 dramatically inhibited cell proliferation, migration, and invasion and reverse EMT process in glioma. LINC01018 directly target to miR-182-5p. Forced up-regulation of miR-182-5p reversed the inhibitory effects on proliferative and metastatic abilities of glioma cells with LINC01018 overexpression. Lastly, the bioinformatics analyses revealed that LINC01018/miR-182-5p axis mediated a cluster of downstream genes (ADRA2C, RAB6B, RAB27B, RAPGEF5, STEAP2, TAGLN3, and UNC13C), which were potential key factors in the development of glioma.LINC01018 inhibits cell proliferation and metastasis in human glioma by targeting miR-182-5p, and should be considered as a potential therapeutic target in this cancer.

Recent studies have demonstrated that several long non-coding RNAs (lncRNAs) play an important role in the occurrence and development of osteosarcoma (OS). However, more lncRNAs and their mechanisms in regulating growth and migration of OS cells remain to be investigated. In this study, we identified an lncRNA called DUXAP10 by analysis of GEO data, which was significantly up-regulated in OS tissues and cell lines. Experiments in vitro revealed that lncRNA DUXAP10 promoted proliferation, migration, and invasion of OS cells and inhibited their apoptosis. We also demonstrated that DUXAP10 promoted the formation and growth of OS by tumor formation assay. Furthermore, SOX18 was identified as a critical downstream target of DUXAP10 by transcriptome RNA-seq. Mechanistically, DUXAP10 mainly localized in cytoplasm and could specifically bind to HuR to increase the stability of SOX18 mRNA. Meanwhile, SOX18 knockdown largely reversed increased proliferation of OS cells induced by DUXAP10 overexpression. Findings from this study indicate that lncRNA DUXAP10 can act as an oncogene in osteosarcoma by binding HuR to up-regulate the expression of SOX18 at a post-transcriptional level, which may provide a new target for OS clinical diagnosis and treatment.

Background: This study intended to investigate the mechanisms underlying the epidermal growth factor receptor (EGFR) mutations in nonsmall cell lung cancer (NSCLC). Materials and Methods: Lung cancer tissue samples were collected from 20 patients with NSCLC (6 EGFR mutation types assigned into 2 categories and 14 EGFR wild types assigned to 4 categories). The samples were subjected to transcriptome sequencing, followed by identification of the differentially expressed mRNAs (DEMs), differentially expressed lncRNAs (DELs), and differentially expressed circRNAs (DECs) between the mutation and nonmutation groups. Function analysis and microRNA (miRNA) prediction for DEMs were performed. The correlations between long noncoding RNA (lncRNA)/circular RNA (circRNA) and messenger RNA (mRNA) were analyzed. In addition, the targeting lncRNA and circRNA of miRNA were predicted. Finally, competing endogenous RNA (ceRNA) network was constructed, and survival analysis for the mRNAs involved in the network was performed. Results: In total, 323 DEMs, 284 DELs, and 224 DECs were identified between EGFR mutation and nonmutation groups. The DEMs were significantly involved in gene ontology functions related to cilium morphogenesis and assembly. ceRNA networks were constructed based on the DEMs, DELs, DECs, and predicted miRNAs. Survival analysis showed that four genes in the ceRNA network, including ABCA3, ATL2, VAMP1, and APLN, were significantly associated with prognosis. The four genes were involved in several ceRNA pathways, including RP1-191J18/circ_000373/miR-520a-5p/ABCA3, RP5-1014D13/let-7i-5p/ATL2, circ_000373/miR-1293/VAMP1, and RP1-191J18/circ_000373/miR-378a-5p/APLN. Conclusion: EGFR mutations in NSCLC may be associated with cilium dysfunction and complex ceRNA regulatory mechanisms. The key RNAs in the ceRNA network may be used as promising biomarkers for predicting EGFR mutations in NSCLC.

Lung cancer is devastating cancer that ranks as the leading cause of cancer-related death. Long noncoding RNA (lncRNA) opioid growth factor receptor pseudogene 1 (OGFRP1) was recognized as an oncogene in many cancers. However, the molecular mechanism of OGFRP1 in lung cancer is still poorly understood. The expression of target RNAs and genes was detected by quantitative real-time PCR and western blot. The interaction between miR-299-3p and OGFRP1 or solute carrier family 38 member 1 (SLC38A1) was predicted by StarbaseV3.0 and verified by dual-luciferase reporter assay and Pearson's correlation coefficient. Besides, a transplantation model of human lung cancer in nude mice was established to evaluate the role of OGFRP1 in lung cancer. OGFRP1 and SLC38A1 were overexpressed, whereas miR-299-3p was lowly expressed in lung cancer tumors and cells. OGFRP1 knockdown suppressed cell proliferation and facilitated ferroptosis by promoting lipid peroxidation and iron accumulation in lung cancer. Besides, Furthermore, miR-299-3p inhibitor or SLC38A1 overexpression attenuated OGFRP1 depletion-induced suppression on cell proliferation and ferroptosis in lung cancer. Animal experiments indicated that OGFRP1 deficiency restrained tumor growth in vivo by regulating the miR-299-3p/SLC38A1 axis. OGFRP1 regulated cell proliferation and ferroptosis in lung cancer by inhibiting miR-299-3p to enhance SLC38A1 expression, providing a novel therapeutic strategy for lung cancer.

Lung cancer is one of the most common malignant tumors with growing morbidity and mortality worldwide. Several treatments are used to manage lung cancer, including surgery, radiotherapy and chemotherapy, as well as molecular-targeted therapy. However, the current measures are still far from satisfactory. Therefore, the current research should focus on exploring the molecular mechanism and then finding an effective treatment. Interestingly, we and others have embarked on a line of investigations focused on the mechanism of lung cancer. Specifically, lncRNA small nucleolar RNA host gene has been shown to be associated with biological characteristics and therapeutic resistance of lung cancer. In addition, small nucleolar RNA host genes may be used as diagnostic biomarker in the future. Herein, we will provide a brief review demonstrating the importance of small nucleolar RNA host genes in lung cancer, especially non-small cell lung cancer. Although lncRNA has shown a crucial role in tumor-related research, a large number of studies are needed to validate its clinical application in the future.

Objectives: This study was to investigate the expression and clinical significance of long intergenic noncoding RNA 00665 (LINC00665) in ovarian cancer , as well as its effect on malignant biological behavior of ovarian cancer cells. Methods: The expressions of LINC00665, miR-148b-3p and KLF5 in ovarian cancer (OC) tissues and cells were detected by RT-qPCR. Western blotting was used to detect KLF5 expression. The expression patterns of LINC00665, U6 and GAPDH in nuclear and cytoplasm fractions were detected using qRT-PCR. Besides, CCK-8 assay, clone formation assay, transwell, scratch test, and flow cytometry were respectively used to detect the cell activity, proliferation, invasiveness, healing of cells, and apoptosis rate of OC cells. Furthermore, the interactions between LINC00665 and miR-148b-3p and between miR-148b-3p and KLF5 were verified by luciferase reporter assay, and the correlations among these three genes were analyzed.Results: LINC00665 expression was up-regulated in ovarian cancer cell lines and tissues. Si-LINC00665 inhibited cell proliferation, invasion and migration, and induced the apoptosis to a certain extent. Subcellular fraction assay revealed the location of LINC00665 was mainly situated in the cytoplasm. Besides, miR-148b-3p was a target of LINC00665, and KLF5 was directly targeted by miR-148b-3p. Si-LINC00665 inhibited KLF5 expression, miR-148b-3p inhibitor promoted KLF5 expression, and si-KLF5 inhibited LINC00665 expression. Interestingly, expressions of LINC00665 and miR-148b-3p, and expressions of miR-148b-3p and KLF5 were negatively correlated, while expressions of LINC00665 and KLF5 were positively correlated. In addition, si-KLF5 inhibited the malignant biological behavior of ovarian cancer cells, while miR-148b-3p inhibitor had the opposite effect. Most importantly, the si-LINC00665 could reverse the promotion effect of miR-148b-3p inhibitor on the malignant biological behavior of ovarian cancer cells.Conclusions: LINC00665 can be used as an effective prognostic indicator of ovarian cancer, which has the potential to be a new drug target.

Long noncoding RNAs have been implicated in many of the hallmarks of cancer. Herein, we found that the expression of lncRNA152 (lnc152; a.k.a. DRAIC), which we annotated previously, is highly upregulated in luminal breast cancer (LBC) and downregulated in triple-negative breast cancer (TNBC). Knockdown of lnc152 promotes cell migration and invasion in LBC cell lines. In contrast, ectopic expression of lnc152 inhibits growth, migration, invasion, and angiogenesis in TNBC cell lines. In mice, lnc152 inhibited the growth of TNBC cell xenografts, as well as metastasis of TNBC cells in an intracardiac injection model. Transcriptome analysis of the xenografts indicated that lnc152 downregulates genes controlling angiogenesis. Using pull down assays followed by LC/MS-MS, we identified RBM47, a known tumor suppressor in breast cancer, as a lnc152-interacting protein. The effects of lnc152 in TNBC cells are mediated, in part, by regulating the expression of RBM47. Collectively, our results demonstrate that lnc152 is an angiogenesis-inhibiting tumor suppressor that attenuates the aggressive cancer-related phenotypes found in TNBC. Implications: This study identifies lncRNA152 as an angiogenesis-inhibiting tumor suppressor that attenuates the aggressive cancer-related phenotypes found in TNBC by upregulating the expression of the tumor suppressor RBM47. As such, lncRNA152 may serve as a biomarker to track aggressiveness of breast cancer, as well as therapeutic target for treating TNBC.

Long non-coding RNA (lncRNA) is a non-protein-coding RNA with a length of more than 200 nucleotides. Studies have shown that lncRNAs have vital impacts on various pathological processes and participate in the development of human diseases, usually through acting as competing endogenous RNAs to modulate miRNA expression and biological functions. lncRNA HOXA Cluster Antisense RNA 3 (HOXA-AS3) was a newly discovered lncRNA and has been demonstrated to be abnormally expressed in many diseases. Moreover, HOXA-AS3 expression was closely correlated with the clinicopathologic characteristics in cancer patients. In addition, HOXA-AS3 exhibited significant properties in regulating several biological processes, including cell proliferation, invasion, and migration. Furthermore, HOXA-AS3 has provided promising values in the diagnosis, prognosis, and therapeutic strategies of several diseases such as liver cancer, glioma, lung cancer, oral cancer, gastric cancer, and even atherosclerosis. In this review, we discuss the abnormal expression of HOXA-AS3 in several human disorders and some pathobiological processes and its clinical characteristics, followed by a summary of HOXA-AS3 functions, regulatory mechanisms, and clinical application potential.

Ferroptosis is a newly-discovered cell death mechanism involved in the progression of various tumors, the role of noncoding RNAs (ncRNAs) in it was relatively less explored. This study identified the low levels of a recently studied long noncoding RNA (lncRNA), A2M-AS1, in pancreatic cancer and suggested its positive correlation with the overall survival time of patients with pancreatic cancer. A2M-AS1 was mainly localized in the cytoplasm, inhibiting the cellular proliferation, migration, and invasion as well as the tumor growth of the pancreatic cancer cells. Moreover, the Erastin-induced ferroptosis increased the expression levels of A2M-AS1. The overexpression of A2M-AS1 promoted ferroptosis in the pancreatic cancer, which was inhibited by the silencing of A2M-AS1. Mechanically, A2M-AS1 could directly interact with the poly (rC) binding protein 3 (PCBP3), which plays an important role in the process of iron metabolism, thereby promoting the ferroptosis in pancreatic cancer. In addition, the A2M-AS1/PCBP3 axis could facilitate the p38 activation and inhibit the phosphorylation of the AKT–mTOR signaling pathway; all these participate in regulating ferroptosis. In conclusion, the regulation of ferroptosis by targeting the A2M-AS1/PCBP3 axis might provide a novel target for the treatment of pancreatic cancer in the future. Implications: A2M-AS1 might be a potential novel therapeutic target for patients with pancreatic cancer in the future.

Noncoding RNAs (ncRNAs) regulation of various diseases including cancer has been extensively studied. Reactive oxidative species (ROS) elevated by oxidative stress are associated with cancer progression and drug resistance, while autophagy serves as an ROS scavenger in cancer cells. However, the regulatory effects of ncRNAs on autophagy and ROS in various cancer cells remains complex. Here, we explore how currently investigated ncRNAs, mainly miRNAs and lncRNAs, are involved in ROS production through modulating antioxidant genes. The regulatory effects of miRNAs and lncRNAs on autophagy-related (ATG) proteins to control autophagy activity in cancer cells are discussed. Moreover, differential expression of ncRNAs in tumor and normal tissues of cancer patients are further analyzed using The Cancer Genome Atlas (TCGA) database. This review hypothesizes links between ATG genes- or antioxidant genes-modulated ncRNAs and ROS production, which might result in tumorigenesis, malignancy, and cancer recurrence. A better understanding of the regulation of ROS and autophagy by ncRNAs might advance the use of ncRNAs as diagnostic and prognostic markers as well as therapeutic targets in cancer therapy.

Background The abnormal expression of long non-coding RNA (lncRNA) Opa-interacting protein 5 antisense RNA 1 (OIP5-AS1) has been observed in many human cancers and the underlying mechanisms have been well studied. However, the function of OIP5-AS1 in acute kidney injury (AKI) remains unclear. Material and methods To explore the role of OIP5-AS1 in the progression of AKI, the cisplatin-induced AKI mouse and cell model were established. To confirm the potential protective effect of OIP5-AS1 during cisplatin-induced AKI, rescue experiments were performed. Targetscan was used to predict the potential targets of miR-144-5p. To further determine whether the effect of miR-144-5p during cisplatin-induced AKI was mediated by PMK2, the recuse experiments using PMK2 overexpressing vector was applied. Results OIP5-AS1 was significantly downregulated both in cisplatin-induced AKI mice and human renal tubular cell line HK-2 cells. Moreover, overexpression of OIP5-AS1 efficiently promoted cell growth and reduced cisplatin-induced apoptosis of HK-2 cells. Furthermore, OIP5-AS1 was identified as a sponge of miR-144-5p, and upregulation of miR-144-5p could significantly reverse overexpression of OIP5-AS1-induced protective effect on the damage of cisplatin to HK-2 cells. In addition, pyruvate kinase M2 (PKM2) was found to be a direct target of miR-144-5p, and overexpression of PKM2 efficiently reversed the effect of miR-144-5p mimics on the damage in cisplatin-stimulated HK-2 cells. Conclusions OIP5-AS1 reduced the apoptosis of cisplatin-stimulated renal epithelial cells by targeting the miR-144-5p/PKM2 axis, which extended the regulatory network of lncRNAs in cisplatin-induced AKI and also provided a novel therapeutic target for AKI treatment.

Understanding of cancer with the help of ever-expanding cutting edge technological tools and bioinformatics is revolutionizing modern cancer research by broadening the space of discovery window of various genomic and epigenomic processes. Genomics data integrated with multi-omics layering have advanced cancer research. Uncovering such layers of genetic mutations/modifications, epigenetic regulation and their role in the complex pathophysiology of cancer progression could lead to novel therapeutic interventions. Although a plethora of literature is available in public domain defining the role of various tumor driver gene mutations, understanding of epigenetic regulation of cancer is still emerging. This review focuses on epigenetic regulation association with the pathogenesis of non-melanoma skin cancer (NMSC). NMSC has higher prevalence in Caucasian populations compared to other races. Due to lack of proper reporting to cancer registries, the incidence rates for NMSC worldwide cannot be accurately estimated. However, this is the most common neoplasm in humans, and millions of new cases per year are reported in the United States alone. In organ transplant recipients, the incidence of NMSC particularly of squamous cell carcinoma (SCC) is very high and these SCCs frequently become metastatic and lethal. Understanding of solar ultraviolet (UV) light-induced damage and impaired DNA repair process leading to DNA mutations and nuclear instability provide an insight into the pathogenesis of metastatic neoplasm. This review discusses the recent advances in the field of epigenetics of NMSCs. Particularly, the role of DNA methylation, histone hyperacetylation and non-coding RNA such as long-chain noncoding (lnc) RNAs, circular RNAs and miRNA in the disease progression are summarized.

Pancreatic cancer is one of the most common causes of cancer death in the world due to the lack of early symptoms, metastasis occurrence and chemoresistance. Therefore, early diagnosis by detection of biomarkers, blockade of metastasis, and overcoming chemoresistance are the effective strategies to improve the survival of pancreatic cancer patients. Accumulating evidence has revealed that long noncoding RNA (lncRNA) and circular RNAs (circRNAs) play essential roles in modulating chemosensitivity in pancreatic cancer. In this review article, we will summarize the role of lncRNAs in drug resistance of pancreatic cancer cells, including HOTTIP, HOTAIR, PVT1, linc-ROR, GAS5, UCA1, DYNC2H1-4, MEG3, TUG1, HOST2, HCP5, SLC7A11-AS1 and CASC2. We also highlight the function of circRNAs, such as circHIPK3 and circ_0000284, in regulation of drug sensitivity of pancreatic cancer cells. Moreover, we describe a number of compounds, including curcumin, genistein, resveratrol, quercetin, and salinomycin, which may modulate the expression of lncRNAs and enhance chemosensitivity in pancreatic cancers. Therefore, targeting specific lncRNAs and cicrRNAs could contribute to reverse chemoresistance of pancreatic cancer cells. We hope this review might stimulate the studies of lncRNAs and cicrRNAs, and develop the new therapeutic strategy via modulating these noncoding RNAs to promote chemosensitivity of pancreatic cancer cells.

Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide. The aim of the present study was to explore the expression level of tumor protein 73 (TP73) in highly malignant CRC tumors and how the long non-coding RNA tumor protein 73 antisense RNA 1 (TP73-AS1) influences that transcription. We found that TP73-AS1 was highly expressed in malignant CRC samples in The Cancer Genome Atlas (TCGA) database. We also demonstrated TP73-AS1 was expressed in thirty samples of CRC tissues collected from China Medical University patients as well as in HCT116, RKO and SW480 CRC cell lines but not in HCoEpiC or CCD-18Co normal colon cells. Only wild-type TP73-AS1, but not any of its alternate splicing isoforms, was positively correlated with tumor malignancy. TP73-AS1 transcripts were shown to be located in cell nuclei especially in close proximity to the TP73 promoter in CRC cells, but not in normal colon cells. In addition, an interaction between lysine demethylase 5A (KDM5A) and TP73-AS1 in CRC cells, but not normal colon cells, and KDM5A localization on the TP73 promoter were influenced by TP73-AS1. Interestingly, the H3K4me3 level on the TP73 promoter was reduced, but was elevated by TP73-AS1 knockdown in CRC cells. In conclusion, these results suggest a novel epigenetic role of TP73-AS1 on histone demethylation that influences TP73 transcription, and shed light on malignancy in CRC.

Cervical cancer is one of the most frequent types of cancer in women, which is characterized by high invasion and metastatic tendency in its advanced stage. Emerging evidence indicated that long non-coding RNAs (LncRNAs) are involved in the pathogenesis of cervical cancer. LINC01287 has been reported to play crucial regulatory roles in the pathogenesis and progression of multiple cancers. However, up until now, whether LINC01287 is associated with the initiation and development of cervical cancer remains largely unknown. In the present study, expression levels of LINC01287, miR-513a-5p and stress-associated endoplasmic reticulum protein 1 (SERP1) mRNA were quantified utilizing qRT-PCR. A series of functional experiments including CCK-8 assay, colony formation assay, transwell assay, flow cytometry, and tumor xenograft growth of cervical cancer cells were performed for studying the effects of LINC01287. The luciferase reporter assay, pull-down assay, and western blot were used to confirm the downstream targets of LINC01287 and miR-513a-5p. The results demonstrate that LINC01287 was highly expressed in cervical cancer tissue samples and cell lines. High LINC01287 predicts a poor prognosis for cervical cancer patients. Additional gain- and loss-of-function experiments demonstrated that silencing LINC01287 inhibited cervical cancer cells proliferation, colony formation, migration, apoptosis in vitro and retarded tumor growth and metastasis in vivo. Furthermore, the dual-luciferase reporter gene system and RNA pulldown assay validated that LINC01287 positively regulated SERP1 expressions by sponging miR-513a-5p, and LINC01287 inhibited cervical cancer progression by regulating miR-513a-5p/SERP1 axis. In conclusion, the current study first identified that LINC01287/miR-513a-5p/SERP1 axis played an important role in cervical cancer progression. LINC01287 might be a prognostic biomarker and a target for new therapies in patients with cervical cancer.

Hepatitis B virus-related hepatocellular carcinoma (HBV-related HCC) is a common, highly invasive malignant tumor associated with a high mortality rate. This study aimed to identify the effective diagnostic and prognostic biomarkers for HBV-related HCC. With HBV-related HCC RNA-sequencing data of The Cancer Genome Atlas (TCGA) database, 159 differentially expressed long noncoding RNAs (lncRNAs) between HBV-related HCC and para-carcinoma normal samples were identified, and 12 lncRNAs were eventually assessed for deeper research. Classification analysis developed a three-lncRNA signature of AC005332.5, ELF3-AS1 and LINC00665, which was demonstrated to be the most discriminatory with an AUC (Area under the curve) value of 0.913 (95% CI: 0.8610-0.9665) and verified in validation patients. The expression levels of AC005332.5, ELF3-AS1 and LINC00665 were significantly changed with different tumor stages or grades. Survival analysis revealed that AC005332.5, ELF3-AS1 and LINC00665 were highly associated with the prognosis of overall survival. Additionally, the lncRNA signature yielded statistical significance to predict clinical outcomes independently from other clinical variables in validation patients, as suggested in the multivariate Cox hazards analysis. Conclusively, a three-lncRNA signature of AC005332.5, ELF3-AS1 and LINC00665 may serve as an excellent diagnostic biomarker for HBV-related HCC and potential prognostic significance for HBV-related HCC sufferers.

Increasing evidence has shown that long non-coding RNAs (lncRNAs), which are non-coding endogenous single-stranded RNAs, play an essential role in various physiological and pathological processes through transcriptional interference, post-transcriptional regulation, and epigenetic modification. Moreover, lncRNAs, as oncogenes or tumor suppressor genes, play an important role in the occurrence and development of human cancers. Prostate androgen-regulated transcript 1 (PART1) was initially identified as a carcinogenic lncRNA in prostate adenomas. The upregulated expression of PART1 plays a tumor-promoting role in liver, prostate, lung cancers, and other tumors. In contrast, the expression of PART1 is downregulated in esophageal squamous cell carcinoma, glioma, and other tumors, which may inhibit the tumor. PART1 plays a dual role in cancer and regulates cell proliferation, apoptosis, invasion, and metastasis through a variety of potential mechanisms. These findings suggest that PART1 is a promising tumor biomarker and therapeutic target. This article reviews the biological functions, related mechanisms, and potential clinical significance of PART1 in a variety of human cancers.

Background: Molecular subtyping of bladder cancer has revealed luminal tumors generally have a more favourable prognosis. However, some aggressive forms of variant histology, including micropapillary, are often classified luminal. In previous work, we found long non-coding RNA (lncRNA) expression profiles could identify a subgroup of luminal bladder tumors with less aggressive biology and better outcomes. Objective: In the present study, we aimed to investigate whether lncRNA expression profiles could identify high-grade T1 micropapillary bladder cancer with differential outcome. Design, setting, and participants: LncRNAs were quantified from RNA-seq data from a HGT1 bladder cancer cohort that was enriched for primary micropapillary cases (15/84). Unsupervised consensus clustering of variant lncRNAs identified a three-cluster solution, which was further characterised using a panel of micropapillary-associated biomarkers, molecular subtypes, gene signatures, and survival analysis. A single-sample genomic signature was trained using lasso-penalized logistic regression to classify micropapillary-like gene-expression, as characterised by lncRNA clustering. The genomic classifier (GC) was tested on luminal tumors derived from the TCGA cohort (N = 202). Outcome measurements and statistical analysis: Patient and tumor characteristics were compared between subgroups by using X2 tests and two-sided Wilcoxon rank-sum tests. Primary endpoints were overall, progression-free and high-grade recurrence-free survival, calculated as the date of high-grade T1 disease at TURBT till date of death from any cause, progression, or recurrence, respectively. Survival rates were estimated using weighted Kaplan–Meier (KM) curves. Results and limitations: Primary micropapillary HGT1 showed decreased FGFR3, SHH, and p53 pathway activity relative to tumors with conventional urothelial carcinoma. Many bladder cancer-associated lncRNAs were downregulated in micropapillary tumors, including UCA1, LINC00152, and MALAT1. Unsupervised consensus clustering resulted in a lncRNA cluster 1 (LC1) with worse prognosis that was enriched for primary micropapillary histology and the Luminal Unstable (LumU) molecular subtype. Interestingly, LC1 appeared to better identify aggressive HGT1 disease, compared to stratifying outcomes using primary histologic characteristics. A signature trained to identify LC1 cases showed good performance in the testing cohort, identifying seven cases with significantly worse survival (p < 0.001). Limitations include the retrospective nature of the study and the lack of a validation cohort. Conclusions: Using the lncRNA transcriptome we identified a subgroup of aggressive HGT1 bladder cancer that was enriched with micropapillary histology. These data suggest that lncRNAs can facilitate the identification of aggressive micropapillary-like tumors, potentially improving patient management.

T-cell acute lymphoblastic leukemia (T-ALL) is a malignancy caused by clonal proliferation of T-cell pre-cursors arising from the thymus. Although the optimized chemotherapy regimen could improve the outcome of such patients, some challenges such as higher risk for induction failure, early relapse and isolated central nervous system (CNS) relapse occurring in T-ALL patients are of great significance, leading to increased mortality rates. Long non-coding RNA (lncRNA) is a key component involved in cell signaling through a variety of mechanisms in regulating gene expression. Oncogenes and tumor suppressors are no exception and their expression can be affected by lncRNAs. In addition, accumulating researches in samples from T-ALL patients as well as pre-clinical studies in mice suggest that the expression profile of lncRNAs in T-ALL could be aberrant, resulting in deregulation of target genes and downstream signaling pathways. In addition, accumulating researches in samples from T-ALL patients as well as pre-clinical studies in mice suggest that the expression profile of lncRNAs in T-ALL could be aberrant, resulting in deregulation of target genes and downstream signaling pathways. These lncRNAs may be determinants of proliferation, apoptosis, and drug resistance observed in T-ALL. Thus, lncRNAs can be a good tool to develop novel strategies against cancer cells in the treatment of relapsed and refractory T-ALL. They can also act as promoting biomarkers in assessing T-ALL and differentiating between patients with poor prognosis and good prognosis.

Somatic copy-number alterations (CNA) promote cancer, but the underlying driver genes may not be comprehensively identified if only the functions of the encoded proteins are considered. mRNAs can act as competitive endogenous RNAs (ceRNA), which sponge miRNAs to posttranscriptionally regulate gene expression in a protein coding–independent manner. We investigated the contribution of ceRNAs to the oncogenic effects of CNAs. Chromosome 1q gains promoted melanoma progression and metastasis at least in part through overexpression of three mRNAs with ceRNA activity: CEP170, NUCKS1, and ZC3H11A. These ceRNAs enhanced melanoma metastasis by sequestering tumor suppressor miRNAs. Orthogonal genetic assays with miRNA inhibitors and target site blockers, along with rescue experiments, demonstrated that miRNA sequestration is critical for the oncogenic effects of CEP170, NUCKS1, and ZC3H11A mRNAs. Furthermore, chromosome 1q ceRNA-mediated miRNA sequestration alleviated the repression of several prometastatic target genes. This regulatory RNA network was evident in other cancer types, suggesting chromosome 1q ceRNA deregulation as a common driver of cancer progression. Taken together, this work demonstrates that ceRNAs mediate the oncogenicity of somatic CNAs. Significance: The function of CEP170, NUCKS1, and ZC3H11A mRNAs as competitive endogenous RNAs that sequester tumor suppressor microRNAs underlies the oncogenic activity of chromosome 1q gains.

Colon cancer is one of the most prevalent malignant tumors across the world. Increasing studies have demonstrated that long non-coding RNAs (lncRNAs) take part in colon cancer development. Our study intends to explore the expression characteristics of LBX2-AS1, a novel lncRNA, in colon cancer and its underlying mechanisms. The results illustrated that LBX2-AS1 level was substantially increased in colon cancer tissues and was obviously correlated with the tumor volume and early distant metastasis of patients. Besides, overexpression of LBX2-AS1 remarkably boosted growth, proliferation, and metastasis and restrained apoptosis in colon cancer cells, whereas LBX2-AS1 knockdown produced the opposite effect. On the other hand, miR-627-5p, down-regulated in colon cancer tissues, was negatively associated with LBX2-AS1 expression. Functional experiments showed that miR-627-5p suppressed colon cancer growth. Mechanistically, LBX2-AS1, as an endogenous competitive RNA, targeted miR-627-5p and restrained its expression, while miR-627-5p targeted and negatively regulated the RAC1/PI3K/AKT axis. Collectively, this study has revealed that LBX2-AS1 is a poor prognostic factor of colon cancer and can regulate colon cancer progression by regulating the miR-627-5p/RAC1/PI3K/AKT pathway.

Breast cancer affects millions of women each year. Despite recent advances in targeted treatments breast cancer remains a significant threat to women’s health. In recent years the development of high-throughput sequencing technologies has advanced the field of transcriptomics shedding light on the role of non-coding RNAs (ncRNAs), including long ncRNAs (lncRNAs), in human cellular function and disease. LncRNAs are classified as transcripts longer than 200nt with no coding potential. These transcripts constitute a diverse group of regulatory molecules essential to the modulation of crucial cellular processes, which dysregulation of leads to disease. LncRNAs exert their regulatory functions through their sequences and by forming complex secondary and tertiary structures that interact with other transcripts, chromatin and/or proteins. Numerous studies have provided evidence of the involvement of LncRNAs in tumor development and disease progression. They possess multiple characteristics that make them novel therapeutic and diagnostic targets. Indeed, the discovery of a novel mechanism by which lncRNAs associated with proteins can induce the formation of phase-separated droplets broadens our understanding of the spatiotemporal control of cellular processes and opens up developing a new treatment. Nevertheless, the role and the molecular mechanisms of many lncRNAs in the regulation of cellular processes and cancer still remain elusive. This is due to the absence of a thorough characterization of the regulatory role of their loci and the functional impact of their aberrations in cancer biology. Here, we present some of the latest advances concerning the role of LncRNAs in breast cancer.

Background: The most prevalent malignant tumor in women is breast cancer (BC). As autophagic therapies have been identified to contribute to BC cell death, the potential prognostic role of long non-coding RNA (lncRNA) related to autophagy in patients with BC was examined. Methods: The lncRNAs expression profiles were derived from The Cancer Genome Atlas (TCGA) database. Throughout univariate Cox regression and multivariate Cox regression test, lncRNA with BC prognosis have been differentially presented. We then defined the optimal cut-off point between high and low-risk groups. The receiver operating characteristic (ROC) curves were drawn to test this signature. In order to examine possible signaling mechanisms linked to these lncRNAs, the Gene Set Enrichment Analysis (GSEA) has been carried out. Results: Based on the lncRNA expression profiles for BC, a 9 lncRNA signature associated with autophagy was developed. The optimal cut-off value for high-risk and low-risk groups was used. The high-risk group had less survival time than the low-risk group. The result of this lncRNA signature was highly sensitive and precise. GSEA study found that the gene sets have been greatly enriched in many cancer pathways. Conclusions: Our signature of 9 lncRNAs related to autophagy has prognostic value for BC, and these lncRNAs related to autophagy may play an important role in BC biology.

Gastrointestinal (GI) cancers presented an alarmingly high number of new cancer cases worldwide and are highly characterised by poor prognosis. The poor overall survival is mainly due to late detection and emerging challenges in treatment, particularly chemoresistance. Thus, the identification of novel molecular targets in GI cancer is highly regarded as the main focus. Recently, long non-coding RNAs (lncRNAs) have been discovered as potential novel molecular targets for combating cancer, as they are highly associated with carcinogenesis and have a great impact on cancer progression. Amongst lncRNAs, HOTTIP has demonstrated a prominent oncogenic regulation in cancer progression, particularly in GI cancers, including oesophageal cancer, gastric cancer, hepatocellular carcinoma, pancreatic cancer, and colorectal cancer. This review aimed to present a focused update on the regulatory roles of HOTTIP in GI cancer progression and chemoresistance, as well as deciphering the associated molecular mechanisms underlying their impact on cancer phenotypes and chemoresistance and the key molecules involved. It has been reported that it regulates the expression of various genes and proteins in GI cancers that impact cellular functions, including proliferation, adhesion, migration and invasion, apoptosis, chemosensitivity, and tumour differentiation. Furthermore, HOTTIP was also discovered to have a higher diagnostic value as compared to existing diagnostic biomarkers. Overall, HOTTIP has presented itself as a novel therapeutic target and potential diagnostic biomarker in the development of GI cancer treatment.

Exosomes (Exos) extracted from human adipose mesenchymal stromal/stem cells (hAD-MSCs) have been reported as therapeutic tools for tissue repair, but how they regulate angiogenesis of endothelial cells remains unknown. In this study, hAD-MSCs were isolated, and early growth response factor-1, Smooth muscle and endothelial cell enriched migration/differentiation-associated long-noncoding RNA (lncRNA-SENCR), and vascular endothelial growth factor-A (VEGF-A) overexpression or knockdown was achieved. Exos extracted from hAD-MSCs (hADSC-Exos) were co-cultured with human umbilical vein endothelial cells (HUVECs) to detect the effects of EGR-1, lncRNA-SENCR, and VEGF-A on angiogenesis and the relationships between EGR-1, lncRNA-SENCR, Dyskerin pseudouridine synthase 1 (DKC1), and VEGF-A. An in vivo experiment verified the effect of hADSC-Exos on the wound healing process. hADSC-Exos substantially promoted the proliferation, migration, and angiogenesis of HUVECs, which could be reversed by short-hairpin RNA SENCR (shSENCR) transfection. hADSC-Exos had elevated expression of EGR-1, which bound to the lncRNA-SENCR promoter. The suppressive effect of Exo-shEGR1 on HUVECs was counteracted by SENCR overexpression. LncRNA-SENCR was shown to interact with DKC1. Overexpression of DKC1 or lncRNA-SENCR maintained stable VEGF-A expression. Overexpression of VEGF-A reversed the suppressive effect of shSENCR on HUVECs. Consistent results were obtained in mice in vivo. Overall, hADSC-Exo EGR-1 upregulates lncRNA-SENCR expression to activate the DKC1/VEGF-A axis, facilitating the wound-healing process by increasing angiogenesis.

Squamous cell carcinomas (SCC) constitute a group of human malignancies that originate from the squamous epithelium. Most patients with SCC experience treatment failure and relapse and have a poor prognosis due to de novo and acquired resistance to first-line chemotherapeutic agents. To identify chemoresistance mechanisms and to explore novel targets for chemosensitization, we performed whole-transcriptome sequencing of paired resistant and parental SCC cells. We identified DLGAP1 antisense RNA 2 (D-AS2) as a crucial noncoding RNA that contributes to chemoresistance in SCC. Mechanistically, D-AS2 affected chromatin accessibility around the histone mark H3K27ac of FAM3 metabolism regulating signaling molecule D (FAM3D), reducing FAM3D mRNA transcription and extracellular protein secretion. FAM3D interacted with the Gαi-coupled G protein–coupled receptors formyl peptide receptor 1 (FPR1) and FPR2 to suppress phospholipase D (PLD) activity, and reduced FAM3D increased PLD signaling. Moreover, activated PLD promoted phosphatidic acid (PA) production and subsequent nuclear translocation of yes-associated protein (YAP). Accordingly, in vivo administration of a D-AS2–targeting antisense oligonucleotide sensitized SCC to cisplatin treatment. In summary, this study shows that D-AS2/FAM3D-mediated PLD/PA lipid signaling is essential for SCC chemoresistance, suggesting D-AS2 can be targeted to sensitize SCC to cytotoxic chemotherapeutic agents. Significance: This study identifies D-AS2 as a targetable lipid-related long noncoding RNA that increases phospholipase D activity to promote YAP signaling, triggering chemoresistance in SCC.

Oral squamous cell carcinoma (OSCC) is an aggressive and common malignancy in the head and neck, characterized by poor prognosis and high incidence. This study aimed to investigate the role of long noncoding RNA TFAP2A-AS1 in OSCC. The competing endogenous RNA network of TFAP2A-AS1 was constructed by bioinformatics analysis. The expressions of miR-1297, TFAP2A-AS1, and TFAP2A were measured by quantitative reverse transcription-polymerase chain reaction. The correlations of TFAP2A-AS1, miR-1297, and TFAP2A with clinicopathological characteristics of OSCC were assessed. RNA immunoprecipitation and dual-luciferase reporter assay were used to identify the target of miR-1297. Cell proliferation was measured by colony formation assay and [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] assay. Transwell assay and wound healing assay were performed to assess cell movement. TFAP2A-AS1 and TFAP2A were upregulated in OSCC and their expression levels were positively correlated. The levels of TFAP2A-AS1, miR-1297, and TFAP2A were also associated with lymphatic metastasis and the tumor-node-metastasis (TNM) stage of OSCC patients. TFAP2A-AS1 acted as a miR-1297 sponge. OSCC cell growth and movement were inhibited by miR-1297. Changes in the miR-1297 expression abolished the effects of TFAP2A-AS1 on OSCC cells. Additionally, TFAP2A was a target of miR-1297. TFAP2A promoted OSCC cell growth and migration/invasion, indicating that TFAP2A mediated the effects of TFAP2A-AS1 and miR-1297. TFAP2A-AS1 exerts an oncogenic effect in OSCC via the TFAP2A-AS1/miR-1297/TFAP2A axis, which may provide new targets and strategies for OSCC treatments.

Breast cancer is the most prevalent cancer diagnosed in women and the major malignancy that threatens women health, thus we explored the role of long noncoding RNA LINC01605 in triple-negative breast cancer (TNBC). We collected tissue samples from TNBC patients and cultured breast cancer cells to detect LINC01605 levels by RT-PCR. We then constructed LINC01605 knockdown and LINC01605 overexpressed TNBC cell lines, cell proliferation was measured by CCK-8 and colony formation assays, cell migration and invasion were measured by Transwell assay, and aerobic glycolysis of cells was detected. Furthermore, a downstream target gene was found, and its role was confirmed by mouse allogeneic tumor formation. It discovered that LINC01605 expression was significantly increased in TNBC patients, and its high expression predicted a low survival prognosis for TNBC patients. Stable knockdown of LINC01605 remarkably inhibited cell proliferation, migration, and invasion, as well as aerobic glycolysis by inhibiting lactate dehydrogenase A in TNBC cell lines. Notably, knockdown of LINC01605 suppressed in vivo tumor formation and migration in TNBC transplanted mice. In conclusion, targeting long noncoding RNA LINC01605 might serve as a therapeutic candidate strategy to treat patients with TNBC.

As potential biomarkers and therapeutic targets, long noncoding RNAs (lncRNAs) are involved in the tumorigenesis of various tumors. Genetic variation in long noncoding regions can lead to lncRNA dysfunction and even cancer. Nevertheless, studies on the association between lncRNA-associated single-nucleotide polymorphisms (SNPs) and the risk of head and neck squamous cell carcinoma (HNSCC) remain inadequate. Here, we aimed to explore the association between SNPs in LINC01614 and HNSCC risk, and the potential role of LINC01614 in tumorigenesis. In this study, we found that rs16854802 A G (odds ratio [OR] = 1.42, 95% confidence interval [CI]: 1.22-1.77, p 0.001) and rs3113503 G C (OR = 1.38, 95% CI: 1.15-1.64, p 0.001) in LINC01614 increased the risk of HNSCC in the Chinese population. Functional bioinformatic analysis and luciferase reporter assay revealed that rs3113503 G C variant disrupted the binding of miRNA-616-3p to LINC01614, which resulted in the increased expression of LINC01614. Further analysis of the TCGA database demonstrated that the upregulated LINC01614 in HNSCC cancer tissues was associated with poor prognostic in HNSCC patients. In vitro experiments showed that knockdown of LINC01614 inhibited the proliferation, invasion, and migration ability of HNSCC cells. Mechanistically, allele C of rs3113503 in LINC01614 was more effective than allele G in activating the PI3K/AKT signaling pathway. Moreover, the reduced expression of LINC01614 also inhibited the activation of the PI3K/AKT signaling pathway. In summary, our findings revealed that the risk SNP rs3113503 G C in LINC01614 altered the binding to miR-616-3p, which led to increased LINC01614 expression and promoted HNSCC progression by activating the PI3K/AKT signaling pathway.

Endoplasmic reticulum stress (ERS) and long non-coding RNAs (lncRNAs) are important in melanoma development and progression. This study aimed to explore the prognostic value of ERS-associated lncRNA profiles in cutaneous melanoma (CM).The Cancer Genome Atlas (TCGA) provides the raw data of CM. GSEA website was used to obtain ERS-related genes, and mRNA and LncRNA co-expression network were used to obtain ERS-related lncRNAs. A Lasso regression analysis was used to identify a prognostic risk model for the composition of ERS-related lncRNAs. Patients were divided into high- and low-risk groups based on the model's risk score. The researchers then compared the two groups' survival rates, immune infiltration, chemotherapeutic drug sensitivity, and immune checkpoint gene expression.Thirty-nine ERS-related lncRNAs were discovered to be prognostic. A prognostic risk model made up of ten ERS-related lncRNAs was discovered. Patients in the low-risk group had a better prognosis than those in the high-risk group. An examination of tumor microenvironment revealed that risk scores correlated with immune cell infiltration in eight cases. Dacarbazine, paclitaxel, and cisplatin, three chemotherapy drugs, were more sensitive in the low-risk group than in the high-risk group.This study identified a risk model of ten ERS-related lncRNAs that have significant prognostic value in CM and could help guide clinical treatment.

Background and aim Glioblastoma multiforme (GBM) is primary brain tumor grade IV characterized by fast cell proliferation, high mortality and morbidity and most lethal gliomas. Molecular approaches underlying its pathogenesis and progression with diagnostic and prognostic value have been an area of interest. Long-non coding RNAs (lncRNAs) aberrantly expressed in GBM have been recently studied. The aim is to investigate the clinical role of lncRNA565 and lncRNA641 in GBM patients. Patients and methods Blood samples were withdrawn from 35 newly diagnosed GBM cases with 15 healthy individuals, then lncRNA565 and lncRNA641 expression were evaluated using real time-PCR. Their diagnostic efficacy was detected using receiver operating characteristic curve. Progression free survival (PFS) and overall survival (OS) were studied using Kaplan–Meier curves. Results lncRNAs expressions were increased significantly among GBM as compared to control group. Their expressions were correlated with clinico-pathological data and survival pattern for the studied GBM patients. Higher levels of both lncRNAs were correlated to worse performance status. Expression of lncRNA565 was increased with large tumor size (≥ 5 cm). Survival analysis showed that both investigated lncRNA were increased with worse PFS and OS. Conclusion Expression of lncRNA565 and lncRNA641 in a liquid biopsy sample can be used as prognostic biomarker for GBM patients.

Triple-negative breast cancer (TNBC) is one of the most malignant subtypes of breast cancer with an unsatisfied prognosis. Effective biomarkers could predict the risk and improve patients' survival. Whether LINC00466 possesses the potential to serve as a biomarker of the progression and prognosis of TNBC was evaluated.A total of 122 TNBC patients were included in this study and provided paired clinical tissues. The expression of LINC00466 in TNBC was evaluated by RT-qPCR and evaluated the clinical significance with a series of statistical analyses. The biological effects and the mechanism were investigated in TNBC cells with CCK8, Transwell, and luciferase reporter assays.LINC00466 was significantly upregulated in TNBC and showed close association with the clinical features of patients, which indicates the development, and severity of patients. LINC00466 functioned as a prognostic biomarker predicting the survival of patients and a tumor promoter improving the proliferation, migration, and invasion of TNBC cells through sponging miR-539-5p.LINC00466 promotes the progression of TNBC via regulating miR-539-5p. The inhibition of LINC00466 might be a novel therapeutic strategy for TNBC.

As a novel group of non-coding RNAs, long non-coding RNA (lncRNAs) can substantially regulate various biological processes. Downregulated tumor-suppressive lncRNAs and upregulated oncogenic lncRNAs (onco-lncRNAs) have been implicated in gastric cancer (GC) development. These dysregulations have been associated with decreased chemosensitivity, inhibited apoptosis, and increased tumor migration in GC. Besides, growing evidence indicates that lncRNAs can be a valuable diagnostic and prognostic biomarker, and their expression levels are substantially associated with the clinicopathological features of affected patients. The current study aims to review the recent findings of the tumor-suppressive lncRNAs and onco-lncRNAs in GC development and highlight their therapeutic, diagnostic, and prognostic values in treating GC cells. Besides, it intends to highlight the future direction of lncRNAs in treating GC.

The tumor microenvironment (TME) is related to chronic inflammation and is currently identified as a risk factor for the occurrence and development of endometrial cancer (EC). Pyroptosis is a new proinflammatory form of programmed cell death that plays a critical role in the progression of multiple diseases. However, the important role of pyroptosis in high-glucose (HG)-related EC and the underlying molecular mechanisms remain elusive. In the present study, transcriptome high-throughput sequencing revealed significantly higher hexokinase domain-containing 1 (HKDC1) expression in EC patients with diabetes than in EC patients with normal glucose. Mechanistically, HKDC1 regulates HG-induced cell pyroptosis by modulating the production of reactive oxygen species and pyroptosis-induced cytokine release in EC. In addition, HKDC1 regulates TME formation by enhancing glycolysis, promoting a metabolic advantage in lactate-rich environments to further accelerate EC progression. Subsequently, miR-876-5p was predicted to target the HKDC1 mRNA, and HOXC-AS2 was identified to potentially inhibit the miR-876-5p/HKDC1 axis in regulating cell pyroptosis in HG-related EC. Collectively, we elucidated the regulatory role of the HOXC-AS2/miR-876-5p/HKDC1 signal transduction axis in EC cell pyroptosis at the molecular level, which may provide an effective therapeutic target for patients with diabetes who are diagnosed with EC.

Although previous studies have revealed that long noncoding RNAs (lncRNAs) regulate the progression of ischemic acute kidney injury (AKI), the exact role and mechanism of lncRNA ENSMUST_147219 in ischemic AKI are not clear. In the present study, lncRNA ENSMUST_147219 was induced by ischemic injury in vitro and in vivo. Functionally, lncRNA ENSMUST_147219 mediated apoptosis in mouse proximal tubule‐derived cell line (BUMPT). Mechanistically, lncRNA ENSMUST_147219 sponged the microRNA (miR)-221-5p to upregulate the expression of interferon regulatory factor 6 (IRF6) to drive apoptosis. Finally, knockdown of lncRNA ENSMUST_147219 markedly attenuated the ischemic AKI by targeting the miR-221-5p/IRF6 axis. Collectively, our data demonstrated that lncRNA ENSMUST_147219 promoted the development of ischemic AKI by regulating the miR-221-5p/IRF6 pathway, which could be considered a new therapeutic target for ischemic AKI.

Long noncoding RNAs (lncRNAs) are implicated in the oncogenesis and metastasis of multiple human cancers. Nonetheless, the precise molecular mechanisms underlying the oncogenic role of lncRNA in esophageal squamous cell carcinoma (ESCC) remains to be clarified.The expression of GK intronic transcript 1 (GK-IT1) was analyzed using ESCC RNA-seq data from The Cancer Genome Atlas database. Quantitative real-time PCR was used to measure the expression of GK-IT1 in ESCC clinical samples and cells. The correlation between GK-IT1 expression and clinicopathological variables was examined using chi-squared tests. Kaplan-Meier survival and Cox regression analyses were employed to generate the survival curve and assess the prognostic value of GK-IT1. Functional experiments were utilized to explore the role of GK-IT1 in promoting cell migration, invasion, proliferation, and suppressing apoptosis and autophagy in ESCC. To understand the mechanism, an RNA pulldown assay, RNA immunoprecipitation, agarose gel electrophoresis, immunofluorescence, and co-immunoprecipitation assays were used.In this study we identified an unreported lncRNA, termed GK-IT1 that was aberrantly overexpressed in ESCC tissues and cells. GK-IT1 was closely associated with advanced clinical stage, and it was an independent prognostic indicator of ESCC. Functional assays verified that GK-IT1 significantly promoted ESCC proliferation, invasion, and migration, and suppressed ESCC apoptosis and autophagy. Furthermore, tumorigenesis experiments in nude mice indicated that GK-IT1 promoted ESCC tumor growth and metastasis. Mechanistically, GK-IT1 competitively bound to mitogen-activated protein kinase 1 (MAPK1) to prevent the interaction between dual specificity phosphatase 6 (DUSP6) and MAPK1, thereby controlling the phosphorylation of MAPK1 and promoting ESCC progression.Our study revealed that GK-IT1 competed with DUSP6 to attenuate the interaction between DUSP6 and MAPK1, leading to activation of the ERK/MAPK pathway, thereby promoting progression of ESCC. Our research indicated that GK-IT1 served as a novel potential target for the diagnosis and treatment of ESCC.

BACKGROUND: Early recurrence is the main obstacle for long-term survival of hepatocellular carcinoma (HCC) patients after curative resection. OBJECTIVE: We aimed to develop a long non-coding RNA (lncRNA) based signature to predict early recurrence. METHODS: Using bioinformatics analysis and quantitative reverse transcription PCR (RT-qPCR), we screened for lncRNA candidates that were abnormally expressed in HCC. The expression levels of candidate lncRNAs were analyzed in HCC tissues from 160 patients who underwent curative resection, and a risk model for the prediction of recurrence within 1 year (early recurrence) of HCC patients was constructed with linear support vector machine (SVM). RESULTS: An lncRNA-based classifier (Clnc), which contained nine differentially expressed lncRNAs including AF339810, AK026286, BC020899, HEIH, HULC, MALAT1, PVT1, uc003fpg, and ZFAS1 was constructed. In the test set, this classifier reliably predicted early recurrence (AUC, 0.675; sensitivity, 72.0%; specificity, 63.1%) with an odds ratio of 4.390 (95% CI, 2.120–9.090). Clnc showed higher accuracy than traditional clinical features, including tumor size, portal vein tumor thrombus (PVTT) in predicting early recurrence (AUC, 0.675 vs 0.523 vs 0.541), and had much higher sensitivity than Barcelona Clinical Liver Cancer (BCLC; 72.0% vs 50.0%), albeit their AUCs were comparable (0.675 vs 0.678). Moreover, combining Clnc with BCLC significantly increased the AUC, compared with Clnc or BCLC alone in predicting early recurrence (all P< 0.05). Finally, logistic and Cox regression analyses suggested that Clnc was an independent prognostic factor and associated with the early recurrence and recurrence-free survival of HCC patients after resection, respectively (all P= 0.001). CONCLUSIONS: Our lncRNA-based classifier Clnc can predict early recurrence of patients undergoing surgical resection of HCC.