Abstract Objective Long non-coding RNAs (lncRNAs) are involved in tumorigenesis. The telomerase RNA component (TERC) is an lncRNA that functions as an essential template for the addition of the telomere repeat.The aims of our study were to determine the biological function and mechanism of TERC in lung adenocarcinoma. Methods RNA-seq analyses were used to compare the expression levels of TERC in cancerous and adjacent normal lung tissues. Functional assays of TERC in LUAD cell lines were performed by siRNA-mediated knockdown. Cell proliferation, migration and invasion were evaluated by WST-1 and transwell assays. Reactive oxygen species (ROS) levels were determined by flow cytometry and examined by fluorescence microscopy, and the morphology of mitochondria was observed using transmission electron microscopy. Protein expression was analyzed by western blot. The formation of autophagosomes was monitored by fluorescence microscopy following expression of fluorescent-tagged LC3. Results RNA-seq analyses show that the expression of TERC is upregulated in lung cancer tissues. Knockdown of TERC inhibits migration and invasion of LUAD cells. Mechanistic analyses indicate that silencing of TERC increases the expression of autophagy-related proteins LC3B, Beclin-1 and AMP-activated protein kinase (AMPK) meanwhile the expression of p62 protein, as well as ferroptosis-regulated proteins GPX4 and SLC7A11 were diminished. Importantly, inhibition of AMPK function counterbalances the effects of TERC knockdown on autophagy and ferroptosis in LUAD cells. Conclusions These findings reveal that suppression of TERC in lung cancer promotes autophagy and ferroptosis via regulation of AMPK. They help to understand the mechanism underlying TERC activity in tumorigenesis.
Background: Long non-coding RNAs (lncRNAs) have involved in human malignancies and played an important role in gene regulations. The dysregulation of lncRNA MIR22HG has been reported in several cancers. However, the role of MIR22HG in esophageal adenocarcinoma (EAC) is poorly understood. Methods: Loss of function approaches were used to investigate the biological role of MIR22HG in EAC cells. The effects of MIR22HG on cell proliferation were evaluated by WST-1 and colony formation assays. The effects of MIR22HGon cell migration and invasion were examined using transwell assays. QRT-PCR and Western blot were used to evaluate the mRNA and protein expression of related genes. Results: In this study, abrogation of MIR22HG inhibited cell proliferation, colony formation, invasion and migration in EAC 3 cell lines (OE33, OE19 and FLO-1). Mechanistically, MIR22HG silencing decreased the expression of STAT3/c-Myc/p-FAK proteins and induced apoptosis in EAC cell lines. Conclusions: These results delineate a novel mechanism of MIR22HG in EAC, and may provide potential targets by developing lncRNA-based therapies for EAC. Funding Statement: This work was supported in part by National Natural Science Foundation of China (NSFC) (81702270 to W.S.; 81871883 to Z.Y.; 81803564 to L.W.); Doctoral Startup Fund in Affiliated Hospital of Guangdong Medical University（Grant No. 2018052638）to W.S.; Guangxi Natural Science Foundation（Grant No. 2015GXNSFBA139117）to L.W.; China Postdoctoral Science Foundation (Grant No. 2018M633619XB) to L.WDeclaration of Interests: No potential conflicts of interest were disclosed.
The role of circular RNA in cancer is emerging. A newly reported circular RNA HIPK3 (circHIPK3) is critical in cell proliferation of various cancer types, although its role in non-small cell lung cancer (NSCLC), has yet to be elucidated. Our results provided evidence that silencing of circHIPK3 significantly impaired cell proliferation, migration, invasion and induced macroautophagy/autophagy. Mechanistically, we uncovered that autophagy was induced upon loss of circHIPK3 via the MIR124-3p-STAT3-PRKAA/AMPKa axis in STK11 mutant lung cancer cell lines (A549 and H838). STAT3 abrogation as well as transfection with a MIR124-3p mimic, recapitulated the induction of autophagy. We also demonstrated antagonistic regulation on autophagy between circHIPK3 and linear HIPK3 (linHIPK3). We therefore propose that the ratio between circHIPK3 and linHIPK3 (C:L ratio) may reflect autophagy levels in cancer cells. We observed that a high C:L ratio (>0.49) was an indicator of poor survival, especially in advanced-stage NSCLC patients. These results support that circHIPK3 is a key autophagy regulator in a subset of lung cancer and has potential clinical use as a prognostic factor. The circular RNA HIPK3 (circHIPK3) functions as an oncogene and autophagy regulator may potential use as a prognostic marker and therapeutic target in lung cancer. Abbreviations 3-MA: 3-methyladenine; AMPK: AMP-activated protein kinase; ATG7: autophagy related 7; Baf-A: bafilomycin A1; BECN1: beclin 1; circHIPK3: circular HIPK3; CQ: chloroquine; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; HIPK3: homeodomain interacting protein kinase 3; IL6R: interleukin 6 receptor; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; NSCLC: non-small cell lung cancer; RFP: red fluorescent protein; RPS6KB1/S6K: ribosomal protein S6 kinase B1; SQSTM1/p62: sequestosome 1; STAT3: signal transducer and activator of transcription 3; STK11: serine/threonine kinase 11
7521^ Background: NSCLC patients whose tumors harbor epidermal growth factor receptor EGFR/HER1 mutations represent a unique subpopulation with unparalleled responsiveness to EGFR tyrosine kinase inhibitors. A phase II study of BIBW 2992 – an oral, novel, potent irreversible inhibitor of EGFR and human HER2 – has completed accrual in Taiwan and the US. Methods: Patients with a stage IIIB/IV lung adenocarcinoma, EGFR mutations in exons 18–21 (by direct sequencing), chemo-naïve or with progressive disease following first-line cytotoxic chemotherapy, measurable disease, and ECOG PS 0–2 received 50 mg or 40 mg BIBW 2992 qd until progression. Response was assessed at 4, 8 and 12 weeks, and at 8-weekly intervals thereafter; images were centrally reviewed. Analysis included primary endpoint objective response rate (ORR) and secondary endpoint progression-free survival (PFS). Results: 444 patients were tested for EGFR mutations and 129 received treatment. Tumor size reduction was seen in 90% of patients. ORR and disease control rate (DCR) was 62% and 94%, respectively, for del19; 52% and 85% for L858R; and 43% and 78% for other mutations based on investigator assessment. L858R mutation was seen in 54 (42%), del19 in 52 (40%) and other mutations in 23 (18%) patients. Median PFS was estimated to be 12 months (95% CI: 10–19.2) for the overall group, 12 months (95% CI: 10–19.2) in del19, 16.3 months (95% CI:10–Inf) in L858R, and 15.6 months (95% CI:10–19.2) when combined. The most common drug-related adverse events (AEs) were diarrhea and rash/acne, as reported in 95% of patients each and were Grade 3 in 18% and 19% of patients, respectively. No Grade 4 cases were reported for these events. Conclusions: Administration of BIBW 2992 resulted in a high ORR, DCR and PFS in NSCLC patients with EGFR mutations. Gastrointestinal and skin disorders were the most frequently observed AEs and were manageable with adequate supportive care and dose reduction. Updated response and PFS data based on independent imaging review will be presented. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Boehringer Ingelheim Boehringer Ingelheim In compliance with the guidelines established by the ASCO Conflict of Interest Policy (J Clin Oncol. 2006 Jan 20;24[3]:519-521) and the Accreditation Council for Continuing Medical Education (ACCME), ASCO strives to promote balance, independence, objectivity, and scientific rigor through disclosure of financial and other interests, and identification and management of potential conflicts. According to the ASCO Conflict of Interest Policy, the following financial and other relationships must be disclosed: employment or leadership position, consultant or advisory role, stock ownership, honoraria, research funding, expert testimony, and other remuneration (J Clin Oncol. 2006 Jan 20;24[3]:520). The ASCO Conflict of Interest Policy disclosure requirements apply to all authors who submit abstracts to the Annual Meeting. For clinical trials that began accrual on or after April 29, 2004, ASCO's Policy places some restrictions on the financial relationships of principal investigators (J Clin Oncol. 2006 Jan 20;24[3]:521). If a principal investigator holds any restricted relationships, his or her abstract will be ineligible for placement in the 2010 Annual Meeting unless the ASCO Ethics Committee grants an exception. Among the circumstances that might justify an exception are that the principal investigator (1) is a widely acknowledged expert in a particular therapeutic area; (2) is the inventor of a unique technology or treatment being evaluated in the clinical trial; or (3) is involved in international clinical oncology research and has acted consistently with recognized international standards of ethics in the conduct of clinical research. NIH-sponsored trials are exempt from the Policy restrictions. Abstracts for which authors requested and have been granted an exception in accordance with ASCO's Policy are designated with a caret symbol (^) in the Annual Meeting Proceedings. For more information about the ASCO Conflict of Interest Policy and the exceptions process, please visit www.asco.org/conflictofinterest.
Hepatocellular carcinoma (HCC) is one of the most common primary cancers with limited therapeutic options. Melatonin, a neuroendocrine hormone produced primarily by the pineal gland, demonstrates an anti-cancer effect on a myriad of cancers including HCC. However, whether melatonin could suppress tumor growth through regulating RNA alternative splicing remains largely unknown. Here we demonstrated that melatonin could inhibit the growth of HCC. Mechanistically, melatonin induced transcriptional alterations of genes, which are involved in DNA replication, DNA metabolic process, DNA repair, response to wounding, steroid metabolic process, and extracellular matrix functions. Importantly, melatonin controlled numerous cancer-related RNA alternative splicing events, regulating mitotic cell cycle, microtubule-based process, kinase activity, DNA metabolic process, GTPase regulator activity functions. The regulatory effect of melatonin on alternative splicing is partially mediated by melatonin receptor MT1. Specifically, melatonin regulates the splicing of IKBKG (NEMO), an essential modulator of NF-κB. In brief, melatonin increased the production of the long isoform of NEMO-L with exon 5 inclusion, thereby inhibiting the growth of HepG2 cells. Collectively, our study provides a novel mechanism of melatonin in regulating RNA alternative splicing, and offers a new perspective for melatonin in the inhibition of cancer progression.
Genome-wide association studies (GWAS) have determined a new single nucleotide polymorphism (SNP) called VTI1A (rs7086803) that induces lung cancer susceptibility in nonsmoking women in Asia. This study aimed to evaluate the association between the VTI1A gene and the susceptibility of Chinese patients to lung cancer; it was also conducted to investigate the relationship between VTI1A SNP and adiponectin receptor 1 expression.A total of 887 subjects were enrolled in this study. VTI1A (rs7086803) genotypes were determined by genotyping. Overall survival (OS) was evaluated using Kaplan-Meier analysis with a log-rank test.Multivariate regression analysis results indicated that the AA genotype of VTI1A (rs7086803) polymorphism was associated with an increased risk of developing non-small cell lung carcinoma (NSCLC) compared with the GG genotype (AA vs. GG: odds ratio [OR] = 2.020; 95% confidence interval [95% CI], 1.033-3.949, p = 0.037). The AA genotype of VTI1A (rs7086803) in smokers predicted significantly shorter OS (median survival time [MST]: AA 9.8 months, AG 19.3 months, GG 12.2 months, p = 0.017). Adiponectin receptor 1 expression in tumor tissues with the AA genotype was significantly lower than that for other genotypes (mean rank: AA 18.55, AG 25, GG 45.76, p = 0.001).The presence of the allele A of VTI1A (rs7086803) may be the allele contributing to the risk of lung cancer susceptibility in Chinese population. Smoking lung cancer patients with the AA genotype of VTI1A gene (rs7086803) had a poor survival rate. Adiponectin receptor 1 expression may be correlated with the susceptibility of the allele A of VTI1A.
Abstract Long non-coding RNAs play critical roles in the development of lung cancer by functioning as tumor suppressors or oncogenes. Changes in the expression of LINC01279 have been associated with cell differentiation and human diseases. However, the mechanism underlying LINC01279 activity in tumorigenesis is not clear. Here, we analyzed the function of LINC01279 in lung adenocarcinoma using clinical samples, xenografts, and non-small-cell lung cancer cell lines. We found that LINC01279 is highly expressed in lung adenocarcinoma and may be considered as a predictive factor for this cancer. Knockdown of LINC01279 prevents tumor growth in xenografts and in cancer cell lines by activating autophagy and apoptosis. Molecularly, we revealed that LINC01279 regulates the expression of focal adhesion kinase and extracellular-regulated kinase signaling. In addition, it complexes with and stabilizes the transcriptional co-repressor SIN3A protein. Suppression of focal adhesion kinase and SIN3A also induces apoptosis and prevents tumor progression, suggesting that they may at least in part mediate the oncogenic activity of LINC01279 . These results identify LINC01279 as a possible oncogene that plays an important role in the development of lung cancer. Our findings provide insights into the mechanism underlying LINC01279 -mediated oncogenesis of lung adenocarcinoma. They may help to discover potential therapeutic targets for cancer diagnosis and prognosis.
According to the newest version of NCCN Clinical Practice Guidelines for Non-Small Cell Lung Cancer (NSCLC), increasing attentions are paid to the role of nodal status and other high-risk factors, including vascular invasion, wedge resection, tumors > 4 cm, visceral pleural involvement, and incomplete lymph node sampling in the individual clinical treatment. Precise definitions of T status and N status, closely associated with prognosis and treatment, are worth expanding further. However, complexity arises because no unity definition exists regarding individual T and N descriptors. In an attempt to explore the potential prognostic values of the T status and N status, we systematically review relevant literature and found that there still remained some disputes about the definitions and prognosis. The adjacent lobe invasion regarded as T2 or T3 has not been reached consensus yet so far. Lymph node spread patterns are associated with the treatment strategies of NSCLC. This review mainly focus on the role of T status and N status and tried to seek appropriate and individual treatment strategies in NSCLC.
Abstract Previous studies have demonstrated a role for long non-coding RNAs in lung adenocarcinoma (LUAD). Here, we found high expression levels of LINC00885 in LUAD, especially in middle and advanced stage disease, by RNA-sequencing analysis. This suggests that LINC00885 may be a potential prognostic biomarker of LUAD. Our functional experiments showed that knocking down LINC00885 expression with small interfering RNAs inhibited the growth, migration, invasion, and autophagy of LUAD cells, blocked cell cycle progression, and promoted cell apoptosis. Additionally, LINC00885 knockdown reduced the protein expression levels of p21, MET, p-mTOR, and p-p70, suggesting that LINC00885 may regulate the growth and metastasis of LUAD through these signaling pathways. Additional experiments revealed that an mTOR activator rescued the inhibited cell growth, invasion, and migration following LINC00885 knockdown. Together, these findings demonstrate that LINC00885 may promote LUAD by regulating p21, MET, and mTOR/p70 signal transduction. This study suggests that LINC00885 may be a prognostic biomarker and therapeutic target in LUAD.
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