The Roles of Antisense Long Noncoding RNAs in Tumorigenesis and Development through Cis-Regulation of Neighbouring Genes.

Antisense long noncoding RNA (as-lncRNA) is a lncRNA transcribed in reverse orientation that is partially or completely complementary to the corresponding sense protein-coding or noncoding genes. As-lncRNAs, one of the natural antisense transcripts (NATs), can regulate the expression of their adjacent sense genes through a variety of mechanisms, affect the biological activities of cells, and further participate in the occurrence and development of a variety of tumours. This study explores the functional roles of as-lncRNAs, which can cis-regulate protein-coding sense genes, in tumour aetiology to understand the occurrence and development of malignant tumours in depth and provide a better theoretical basis for tumour therapy targeting lncRNAs.

Identifying autophagy-related genes as potential targets for immunotherapy in tuberculosis.

PURPOSE: Identifying of host-directed targets and molecular markers of immune response for tuberculosis (TB) immunotherapy is urgent and meaningful. Previous studies have demonstrated an important role of autophagy in the course and pathophysiology of TB and is associated with the efficacy of TB treatment. However, its role in TB immunotherapy is still incomplete. METHODS: The effect of autophagy on intracellular bacteria load was examined in sulforaphane (SFN)-treated THP-1 cells. The immune infiltration was assessed based on public databases. Functional enrichment analysis revealed the pathways involved. LASSO Cox regression analysis was employed to identify hub genes. Moreover, machine learning analysis was used to obtain important targets of TB immunotherapy. Finally, the relationship between hub genes and immune infiltration was assessed, as well as the relevance of chemokines. RESULTS: We found that SFN reduced intracellular bacteria load by enhancing autophagy in THP-1 cells. Thirty-two autophagy-related genes (ARGs) were identified, three types of immune cells (macrophages, neutrophils, and DC cells) were significantly enriched in TB patients, and 6 hub genes (RAB5A, SQSTM1, MYC, MAPK8, MAPK3, and FOXO1) were closely related to TB immune infiltration. The 32 ARGs were mainly involved in autophagy, apoptosis, and tuberculosis pathways. FOXO1, SQSTM1, and RAB5A were identified as important target genes according to the ranking of variable importance, with FOXO1 being a potential autophagy-related target of TB immunotherapy. CONCLUSION: This study highlights the association between autophagy-related genes and immune infiltration in TB. Three key genes, especially FOXO1, regulated by SFN, will provide new insights into diagnostic and immunotherapy strategies for clinical tuberculosis.

PI3K-AKT-Targeting Breast Cancer Treatments: Natural Products and Synthetic Compounds.

Breast cancer is the most commonly diagnosed cancer in women. The high incidence of breast cancer, which is continuing to rise, makes treatment a significant challenge. The PI3K-AKT pathway and its downstream targets influence various cellular processes. In recent years, mounting evidence has shown that natural products and synthetic drugs targeting PI3K-AKT signaling have the potential to treat breast cancer. In this review, we discuss the role of the PI3K-AKT signaling pathway in the occurrence and development of breast cancer and highlight PI3K-AKT-targeting natural products and drugs in clinical trials for the treatment of breast cancer.

Non-Lactobacillus dominance of the vagina is associated with reduced live birth rate following IVF/ICSI: a propensity score-matched cohort study.

PURPOSE: Whether the dominant status of vaginal Lactobacillus is associated with IVF/ICSI outcomes. METHODS: This is a propensity score-matched retrospective cohort study consists of 2285 women undergoing their first fresh autologous IVF cycles. We divided the patients into the Lactobacillus-dominant group and non-Lactobacillus-dominant group based on the abundance of Lactobacillus in Gram-stained vaginal smear examined by microscopy. We compared IVF outcomes between the two groups. We matched Lactobacillus-dominant women with non-Lactobacillus-dominant women by propensity score (PS) to reduce the impact of confounding factors. We evaluated the effect of vaginal Lactobacillus on live birth using univariate and multivariate analysis models. We also conducted interaction and stratified analyses. RESULTS: Compare to the Lactobacillus-dominant group, the biochemical pregnancy rate (50.12% vs. 57.61%, P = 0.03), clinical pregnancy rate (40.98% vs. 50.82%, P < 0.01), and live birth rate (31.83% vs. 41.22%, P < 0.01) were significantly lower in the non-Lactobacillus-dominant group, the preclinical pregnancy loss rate (18.22% vs. 11.79%, P = 0.05) and preterm birth rate (33.09% vs. 21.59%, P = 0.02) were significantly higher in the non-Lactobacillus-dominant group. However, the miscarriage rate (18.86% vs. 15.67%, P = 0.40) and ectopic pregnancy rate (1.41% vs.1.64%, P = 0.78) were similar between the two groups. Loss dominance of Lactobacillus in the vagina was an independent risk factor for live birth (OR 0.66, 95% CI 0.50-0.88). CONCLUSIONS: Loss dominance of Lactobacillus in the vagina negatively affects IVF outcomes by decreasing the chances of pregnancy and live birth, increasing risks of preclinical pregnancy loss and preterm birth.

Proteasome inhibitors decrease paclitaxel­induced cell death in nasopharyngeal carcinoma with the accumulation of CDK1/cyclin B1.

Southeast Asia is a region with high incidence of nasopharyngeal carcinoma (NPC). Paclitaxel is the mainstay for the treatment of advanced nasopharyngeal cancer. The present study investigated the effect of proteasome inhibitors on the therapeutic effect of paclitaxel and its related mechanism. The present data from Cell Counting Kit­8 and flow cytometry assays demonstrated that appropriate concentrations of proteasome inhibitors (30 nM PS341 or 700 nM MG132) reduced the lethal effect of paclitaxel on the nasopharyngeal cancer cells. While 400 nM paclitaxel effectively inhibited cell division and induced cell death, proteasome inhibitors (PS341 30 nM or MG132 700 nM) could reverse these effects. Additionally, the western blotting results demonstrated accumulation of cell cycle regulation protein CDK1 and cyclin B1 in proteasome inhibitor­treated cells. In addition, proteasome inhibitors combined with paclitaxel led to decreased MCL1 apoptosis regulator, BCL2 family member/Caspase­9/poly (ADP­ribose) polymerase apoptosis signaling triggered by CDK1/cyclin B1. Therefore, dysfunction of CDK1/cyclin B1 could be defining the loss of paclitaxel lethality against cancer cells, a phenomenon affirmed by the CDK1 inhibitor Ro3306. Overall, the present results demonstrated that a combination of paclitaxel with proteasome inhibitors or CDK1 inhibitors is antagonistic to effective clinical management of NPC.

A Novel Biological Activity of the STAT3 Inhibitor Stattic in Inhibiting Glutathione Reductase and Suppressing the Tumorigenicity of Human Cervical Cancer Cells via a ROS-Dependent Pathway.

INTRODUCTION: Glutathione reductase (GSR) provides reduced glutathione (GSH) to maintain redox homeostasis. Inhibition of GSR disrupts this balance, resulting in cell damage, which benefits cancer therapy. However, the effect of GSR inhibition on the tumorigenicity of human cervical cancer is not fully understood. MATERIALS AND METHODS: Tissue microarray analysis was employed to determine GSR expression in cervical cancer tissues by immunohistochemical staining. Cell death was measured with PI/FITC-annexin V staining. mRNA levels were measured via quantitative RT-PCR. Protein expression was measured by Western blotting and flow cytometry. STAT3 deletion was performed with CRISPR/Cas9 technology. GSR knockdown was achieved by RNA interference. Reactive oxygen species (ROS) levels were measured by DCF staining. GSR enzymatic activity was measured with a GSR assay kit. The effect of GSR inhibition on the growth of tumors formed by cervical cancer cells was investigated using a xenograft model. RESULTS: The expression of GSR was increased in human cervical cancer tissues, as shown by immunohistochemical staining. GSR knockdown by RNA interference in human cervical cancer cell lines resulted in cell death, suggesting the ability of GSR to maintain cancer cell survival. The STAT3 inhibitor 6-nitrobenzo[b]thiophene 1,1-dioxide (Stattic) also inhibited the enzymatic activity of GSR and induced the death of cervical cancer cells. More importantly, Stattic decreased the growth of xenograft tumors formed by cervical cancer cells in nude mice. Mechanistically, tumor cell death induced by Stattic-mediated GSR inhibition was ROS-dependent, since the ROS scavengers GSH and N-acetyl cysteine (NAC) reversed the effect of Stattic. In contrast, pharmacological and molecular inhibition of STAT3 did not induce the death of cervical cancer cells, suggesting a STAT3-independent activity of Stattic. CONCLUSION: Stattic inhibits the enzymatic activity of GSR and induces STAT3-independent but ROS-dependent death of cervical cancer cells, suggesting its potential application as a therapeutic agent for human cervical cancers.

miR-485-3p regulated by MALAT1 inhibits osteosarcoma glycolysis and metastasis by directly suppressing c-MET and AKT3/mTOR signalling.

AIMS: Osteosarcoma (OS) is an extremely malignant bone cancer with high incidence and rapid progression. This study aims to investigate the role and underlying mechanisms of MALAT1 and miR-485-3p in OS. MATERIALS AND METHODS: qRT-PCR and Western blotting were utilized to measure the levels of miR-485-3p, MALAT1, c-MET, AKT3, p-mTOR, mTOR, glycolysis-related proteins or migration-related proteins. Colony formation and transwell assay were used to test the roles of miR-485-3p, MALAT1, c-MET and AKT3 in cancer cell proliferation, migration and invasion. Dual luciferase assay was used to validate the interactions of miR-485-3p/c-MET, miR-485-3p/AKT3, and MALAT1/miR-485-3p. Glucose uptake assay and measurement of lactate production were employed to determine the glycolysis process. Mouse tumour xenograft model was used to determine the effect of shMALAT1 and miR-485-3p mimics on tumour growth and metastasis in vivo. KEY FINDINGS: miR-485-3p was decreased while c-MET, AKT3, and MALAT1 were increased in human OS tissues and cells. miR-485-3p bound directly to c-MET and AKT3 mRNAs and repressed OS cell glycolysis, proliferation, migration, and invasion through decreasing glycolysis-related proteins and migration-related proteins via inhibiting c-MET and AKT3/mTOR pathway. In addition, MALAT1 interacted with miR-485-3p and disinhibited c-MET and AKT3/mTOR signalling. Knockdown MALAT1 or overexpression of miR-485-3p restrained OS tumour growth and lung metastasis in vivo. SIGNIFICANCE: miR-485-3p suppresses OS glycolysis, proliferation, and metastasis via inhibiting c-MET and AKT3/mTOR signalling and MALAT1 acts as a sponge of miR-485-3p. MALAT1 and miR-485-3p may be the key regulators in OS progression, and potential molecular targets for future OS therapy.

Pharmacological inhibition of GSK3 promotes TNFα-induced GM-CSF via up-regulation of ERK signaling in nasopharyngeal carcinoma (NPC).

Granulocyte-macrophage colony stimulating factor (GM-CSF) functions to drive nasopharyngeal cancer (NPC) metastasis via recruitment and activation of macrophages. However, the source and the regulation of GM-CSF in tumor microenvironment of NPC are not fully understood. In this study, we found that TNFα induced GM-CSF production in NPC CNE1, CNE2, and 5-8F cells in time- and dose-dependent manners. GM-CSF production was tolerant, because the pre-treatment of NPC cells with TNFα down-regulated the GM-CSF production induced by TNFα re-treatment. TNFα activated glycogen synthase kinase-3 (GSK-3), which is an enzyme to regulate glycogen synthesis, and also is a critical downstream element of the PI3K/Akt to regulate cell survival. GSK3 inhibitors up-regulated TNFα-induced GM-CSF, and reversed GM-CSF tolerance induced by TNFα pre-treatment, suggesting that GSK3 activation down-regulated GM-CSF production. GM-CSF down-regulation was not related to ubiquitin-editing enzyme A20. The over-expression of A20 did not regulate GM-CSF production induced by TNFα. However, GSK3 inhibitors up-regulated ERK activation, which contributed to the production of GM-CSF induced by TNFα, suggesting that GSK3 negatively regulated TNFα-induced GM-CSF via down-regulation of ERK signaling. Taking together, these results suggested that GSK3 pathway may be a target for the regulation of TNFα-induced GM-CSF in the tumor microenvironment.

H19 regulates angiogenic capacity of extravillous trophoblasts by H19/miR-106a-5p/VEGFA axis.

PURPOSE: To investigate the role and underlying mechanism of H19 in regulating angiogenic capacity of extravillous trophoblasts. METHODS: Gain and loss of function experiments were performed using a human first-trimester extravillous trophoblast (EVT) cell line, HTR-8/SVneo cells. H19 was overexpressed or knocked down in HTR-8 cells by transfecting plasmid harboring whole-length H19 sequence (pH19) or siRNA specially targeting H19, respectively (siH19). Cell migration and tube-formation assay were assessed in the indicated groups. Gene expression was detected by RT-qPCR, Western blot, and ELISA assay. RESULTS: Overexpression of H19 in EVT cells increased cell migration and tube formation, while downregulation of H19 in EVT cells decreased cell migration and tube formation. Furthermore, we found that H19 played its role by VEGFA. In addition, we demonstrated the H19/miR-106a-5p/VEGFA regulatory axis in EVT. Experiments of the clinical specimen showed that H19 was very abundantly expressed in human first-trimester trophoblasts, and we found that the expression of H19 and VEGFA were significantly downregulated in the villous tissues from idiopathic recurrent miscarriage (RM) patients; moreover, the expression of H19 and VEGFA was positively correlated. CONCLUSION: H19/miR-106a-5p/VEGFA axis plays a role in regulating the angiogenic capacity of EVT, which might contribute to idiopathic RM.

IL-1α and IL-1ß promote NOD2-induced immune responses by enhancing MAPK signaling.

Both toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) induce a tightly regulated inflammatory response at risk of causing tissue damage, depending on the effectiveness of ensuing negative feedback regulatory mechanisms. Cross-regulation between TLRs, NLRs, and cytokine receptors has been observed. However, the cross-regulation between interleukin-1 (IL-1) receptors and NOD2 is not completely understood. In this study, we found that IL-1α/ß increased NOD2-induced inflammatory response in human monocytic THP1 cells, peripheral blood mononuclear cells (PBMCs), mouse macrophage RWA264.7 cells and spleen cells, and in an in vivo experiment. IL-1α/ß pre-treatment induced the production of CXC chemokines, including growth-regulated oncogene (GRO)-α, GRO-ß, and IL-8, and proinflammatory cytokines, including IL-1ß, IL-6, and TNFα, which are induced by the activation of NOD2, in a dose- and time-dependent manner. However, pre-treatment with the NOD2 ligand muramyl dipeptide (MDP) did not up-regulate the expression of cytokines induced by IL-1α/ß re-treatment. IL-1ß treatment increased the expression of A20, which is an important inhibitor of the innate immune response. However, the overexpression of A20 failed to inhibit MDP-induced cytokine production, suggesting that A20 had no effects on the NOD2-induced immune response. In addition, IL-1α/ß increased the expression of NOD2 and its downstream adaptor RIP2, and IL-1α/ß pre-treatment increased MDP-induced activation of mitogen-activated protein kinases (MAPKs), including ERK, JNK, and P38, which contributed to MDP-induced cytokine production. Based on these results, IL-1α/ß promote the NOD2-induced immune responses by enhancing MDP-induced activation of MAPK signaling pathways.

Super-Enhancer-Associated Long Noncoding RNA HCCL5 Is Activated by ZEB1 and Promotes the Malignancy of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most dominant causes of neoplasm-related deaths worldwide. In this study, we identify and characterize HCCL5, a novel cytoplasmic long noncoding RNA (lncRNA), as a crucial oncogene in HCC. HCCL5 promoted cell growth, G1-S transition, invasion, and metastasis while inhibiting apoptosis of HCC cells both in vitro and in vivo. Moreover, HCCL5 was upregulated in TGF-ß1-induced classical epithelial-to-mesenchymal transition (EMT) models, and this lncRNA in turn accelerated the EMT phenotype by upregulating the expression of transcription factors Snail, Slug, ZEB1, and Twist1. HCCL5 was transcriptionally driven by ZEB1 via a super-enhancer and was significantly and frequently overexpressed in human HCC tissues, correlating with worse overall survival of patients with HCC. Together, this study characterizes HCCL5 as a super-enhancer-driven lncRNA promoting HCC cell viability, migration, and EMT. Our data also suggest that HCCL5 may serve as a novel prognostic biomarker and therapeutic target in HCC. SIGNIFICANCE: These findings identify the lncRNA HCCL5 as a super-enhancer-driven oncogenic factor that promotes the malignancy of hepatocellular carcinoma.

The activation of Toll-like receptor 4 reverses tumor differentiation in human glioma U251 cells via Notch pathway.

Toll-like receptors (TLRs) are closely related to cancer. However, the mechanism for TLR regulation of cancer is not fully understood. Our previous studies demonstrated that toll-like receptor (TLR) 4 functions to maintain the un-differential stem cell phenotypes of human endothelial progenitor cells. In this study, we found that human glioma cells expressed several TLRs. The activation of TLR4 by LPS in glioma U251 cells induced the expression of cytokines, including IL-1ß, IL-6, IL-8, and TNFα, suggesting the functional expression of TLR4. Nude mouse in vivo studies showed that LPS treatment promoted tumor growth, and decreased mouse survival. But LPS treatment did not promote tumor cell proliferation in vitro. Meanwhile, we found that LPS treatment down-regulated the expression of glial fibrillary acidic protein (GFAP), an important differentiation maker of glioma, at both mRNA and protein levels. TLR4 activation also down-regulated GFAP in glioma Hs683 cells. LPS did not induce the activation of MAPKs, but induced the activation of NF-κB. However, pharmacological inhibition of NF-κB signaling did not reverse the down-regulation of GFAP. Furthermore, we found that LPS induced the activation of Notch pathway, which was MyD88-dependent, and Notch inhibition reversed the down-regulation of GFAP. In addition, LPS treatment up-regulated stem cell makers, including CD34 and CD133. Taken together, these results suggested that in human glioma U251 cells, TLR4 functions to reverse tumor differentiation, and it may be a target for glioma prevention and therapy.

STC1 promotes cell apoptosis via NF-κB phospho-P65 Ser536 in cervical cancer cells.

Stanniocalin-1 (STC1) is a secreted glycoprotein hormone and involved in various types of human malignancies. Our previous studies revealed that STC1 inhibited cell proliferation and invasion of cervical cancer cells through NF-κB P65 activation, but the mechanism is poorly understood. In our studies, we found overexpression of STC1 promoted cell apoptosis while silencing of STC1 promoted cell growth of cervical cancer. Phospho-protein profiling and Western blotting results showed the expression of NF-κB related phosphorylation sites including NF-κB P65 (Ser536), IκBα, IKKß, PI3K, and AKT was altered in STC1-overexpressed cervical cancer cells. Moreover, PI3K inhibitor LY294002, AKT-shRNA and IκBα-shRNA could decrease the protein content of phospho-P65 (Ser536), phospho-IκBα, phospho-AKT and phospho-IKKß while increasing the level of P65 compared to STC1 overexpression groups in cervical cancer cells. Also, PI3K inhibitor LY294002, AKT-shRNA and IκBα-shRNA elevated the percentage of apoptosis and suppressed the G1/S transition in those cells. Additionally, STC1 level was decreased in cervical cancer, especial in stage II and III. The results of immunohistochemistry for the cervical cancer microarray showed that a lower level of STC1, phospho-PI3K and P65 protein expression in tumor tissues than that in normal tissues, and a higher level of phospho-P65 protein expression in tumor tissues, which is consistent with the results of the Western blotting. These data demonstrated that STC1 can promote cell apoptosis via NF-κB phospho-P65 (Ser536) by PI3K/AKT, IκBα and IKK signaling in cervical cancer cells. Our results offer the first mechanism that explains the link between STC1 and cell apoptosis in cervical cancer.

DNMT3A R882 Mutations Predict a Poor Prognosis in AML: A Meta-Analysis From 4474 Patients.

DNA (cytosine-5)-methyltransferase 3 alpha (DNMT3A) mutations were widely believed to be independently associated with inferior prognosis in acute myeloid leukemia (AML) patients. As dominant missense alterations in DNMT3A mutations, R882 mutations cause the focal hypomethylation phenotype. However, there remains debate on the influence of R882 mutations on AML prognosis. Thus, this meta-analysis aimed at further illustrating the prognostic power of DNMT3A R882 mutations in AML patients.Eligible studies were identified from 5 databases containing PubMed, Embase, Web of Science, Clinical Trials, and the Cochrane Library (up to October 25, 2015). Effects (hazard ratios [HRs] with 95% confidence interval [CI]) of relapse-free survival (RFS) and overall survival (OS) were pooled to estimate the prognostic power of mutant DNMT3A R882 in overall patients and subgroups of AML patients.Eight competent studies with 4474 AML patients including 694 with DNMT3A R882 mutations were included. AML patients with DNMT3A R882 mutations showed significant shorter RFS (HR = 1.40, 95% CI = 1.24-1.59, P < 0.001) and OS (HR = 1.47, 95% CI = 1.17-1.86, P = 0.001) in the overall population. DNMT3A R882 mutations predicted worse RFS and OS among the subgroups of patients under age 60 (RFS: HR = 1.44, 95% CI = 1.25-1.66, P < 0.001; OS: HR = 1.48, 95% CI = 1.15-1.90, P = 0.002), over age 60 (RFS: HR = 2.03, 95% CI = 1.40-2.93, P < 0.001; OS: HR = 1.85, 95% CI = 1.36-2.53, P < 0.001), cytogenetically normal (CN)-AML (RFS: HR = 1.52, 95% CI = 1.26-1.83, P < 0.001; OS: HR = 1.67, 95% CI = 1.16-2.41, P = 0.006), and non-CN-AML (RFS: HR = 1.96, 95% CI = 1.20-3.21, P = 0.006; OS: HR = 2.51, 95% CI = 1.52-4.15, P = 0.0038).DNMT3A R882 mutations possessed significant unfavorable prognostic influence on RFS and OS in AML patients.

Lnc-CC3 increases metastasis in cervical cancer by increasing Slug expression.

Although screening has reduced mortality rates, metastasis still results in poor survival and prognosis in cervical cancer patients. We compared cervical cancer ESTs libraries with other ESTs libraries to identify candidate genes and cloned a novel cervical cancer-associated lncRNA, lnc-CC3. Overexpression of lnc-CC3 promoted migration and invasion by SiHa cervical cancer cells in vitro and in vivo, increased Slug expression, and reduced the expression of the epithelial cell marker E-cadherin. Conversely, lnc-CC3 knockdown altered SiHa cell morphology and increased the expression of E-cadherin, thereby suppressing migration and invasion. These results suggest lnc-CC3 may be a useful marker of metastasis in cervical cancer.

Down-regulation of MALAT1 inhibits cervical cancer cell invasion and metastasis by inhibition of epithelial-mesenchymal transition.

The metastasis-associated lung adenocarcinoma transcript 1(MALAT1), a member of the long non-coding RNA (lncRNA) family, has been reported to be highly enriched in many kinds of cancers and to be a metastasis marker and a prognostic factor. In this study, we found that MALAT1 expression levels were significantly increased in cervical cancer (CC) cells and tissues. The down-regulation of MALAT1 by shRNA in CC cells inhibited the invasion and metastasis in vitro and in vivo. Microarray analysis showed that the knockdown of MALAT1 up-regulated the epithelial markers E-cadherin and ZO-1, and down-regulated the mesenchymal markers ß-catenin and Vimentin. This regulation was further confirmed by subsequent observation from RT-PCR, western blot, and immunofluorescence results. Meanwhile, the transcription factor snail, which functions to modulate epithelial-mesenchymal transition (EMT), was also down-regulated at both transcript and protein levels by MALAT1 down-regulation. In addition, we found that MALAT1 expression levels were positively related to HPV infection in cervical epithelial tissues by microarray analysis. Taken together, these results suggest that MALAT1 functions to promote cervical cancer invasion and metastasis via induction of EMT, and it may be a target for the prevention and therapy of cervical cancers.

LncRNAs: key players and novel insights into cervical cancer.

Cervical cancer contributed the second highest number of deaths in female cancers, exceeded only by breast cancer, carrying high risks of morbidity and mortality. There was a great need and urgency in searching novel treatment targets and prognosis biomarkers to improve the survival rate of cervical cancer patients. Many long non-coding RNAs (lncRNAs) were emerging as pivotal regulators in various biological processes and took vitally an effect on the oncogenesis and progression of cervical cancer. In this review, we summarized the origin and overview function of lncRNAs; highlighted the roles of lncRNAs in cervical cancer in terms of prognosis and tumor progression, invasion and metastasis, apoptosis, and radio-resistance; and outlined the molecular mechanisms of lncRNAs in cervical cancer from the aspects of the interaction of lncRNAs with proteins/mRNAs (especially in HPV protein) and miRNAs, as well as RNA N-methyladenosine (m6A) methylation of lncRNAs. Meanwhile, the application of lncRNAs as biomarkers in cervical cancer prognosis and predictors for metastasis was also discussed. An overview of these researches will be valuable for broadening horizons into mechanisms, selection of meritorious biomarkers for diagnosis as well as prognosis, and future targeted therapy of cervical cancer.

The role of MALAT1 correlates with HPV in cervical cancer.

Cervical cancer, the second most common type of cancer in women worldwide, is responsible for >275,100 mortalities each year and is associated with high-risk human papilloma virus (HR-HPV). HPVs have two important oncogenes, E6 and E7, which have crucial roles in malignant transformation in cervical cancer. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a long non-coding RNA originally identified in non-small cell lung cancer. Previous studies have revealed that MALAT1 is expressed in numerous tissue types, and is significant in maintaining the normal function of the body. However, it also appeared to be notably upregulated in numerous carcinoma types compared with adjacent non-cancerous tissues. In the present study, it was identified that MALAT1 expression was upregulated in cervical cancer cell lines compared with normal cervical squamous cell samples. Further study into the effect of MALAT1 on cellular phenotype revealed that MALAT1 was able to promote cell migration and proliferation. Of note, it was revealed that the expression of MALAT1 was decreased with the knockdown of HPV16 E6/E7 in CaSki cells. Furthermore, the investigations in clinical samples also revealed that MALAT1 was expressed in HPV-positive cervical squamous cells, but not in HPV-negative normal cervical squamous cells. These results indicate that HPV correlates with MALAT1 deregulation in cervical cancer.