scholarly journals MicroRNA-520a discourages lung cancer pathogenesis and progression involving the downregulation of RRM2 and Wnt signaling deficits

2020 ◽  
Author(s):  
Yi Xie ◽  
Congyu Xue ◽  
Shuai Guo ◽  
Lei Yang
Keyword(s):  
Lung Cancer ◽  
Survival Rate ◽  
Wnt Signaling ◽  
Cell Lines ◽  
Cancer Progression ◽  
Altered Expression ◽  
Cancer Pathogenesis ◽  
Tumor Growth And Metastasis

Abstract Background Increasingly evidence has noted the critical functions of microRNAs (miRNAs) in disease control including cancer progression. This paper aimed to explore the functions of miR-520a in lung cancer (LC) and the downstream molecules implicated. Methods Aberrantly expressed miRNAs in LC tissues were screened out by miRNA microarrays. miR-520a expression in LC tissues and cell lines was determined, and the correlation between miR-520a level and survival rate of patients was analyzed. Altered expression of miR-520a was introduced to evaluate its function in LC cell malignant behaviors. The target mRNA and the potential signaling pathway mediated by miR-520a were figured out. Xenograft tumors were induced in mice to test the role of miR-520a in tumorigenesis in vivo. Results Poor expression of miR-520a was found in LC tissues and cell lines. A higher miR-520a level indicated a better survival rate in LC patients. Overexpression of miR-520a led to declines in cell viability, proliferation, migration, invasion and resistance to apoptosis. The target mRNAs of miR-520a were enriched on the Wnt signaling. miR-520a inactivated the Wnt pathway. miR-520a could bind to RRM2 and downregulate RRM2 expression in LC cells. Overexpression of RRM2 promoted the malignant behaviors of cancer cells, but this promotion was inhibited by miR-520a. Overexpression of miR-520a also inhibited the tumor growth and metastasis in nude mice. Conclusion The present study provided evidence that miR-520a could inhibit LC progression through RRM2 down-regulation and Wnt signaling deficit. This paper may offer novel ideas concerning LC treatment.

scholarly journals Role of lung and gut microbiota on lung cancer pathogenesis

2021 ◽  
Author(s):  
Yue Zhao ◽  
Yuxia Liu ◽  
Shuang Li ◽  
Zhaoyun Peng ◽  
Xiantao Liu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Gut Microbiota ◽  
Cancer Progression ◽  
Gut Microbiome ◽  
Intestinal Flora ◽  
Inflammatory Factors ◽  
Cancer Pathogenesis ◽  
Research Findings ◽  
Relationship Of

Abstract Background Lung cancer is the leading cause of cancer-related deaths worldwide (Ferlay et al., Int J Cancer 136:E359–386, 2015). In addition, lung cancer is associated with the highest mortality among all cancer types (Wu et al., Exp Ther Med 16:3004–3010, 2018). Previous studies report that microbiota play an important role in lung cancer. Notably, changes in lung and gut microbiota, are associated with progression of lung cancer. Several studies report that lung and gut microbiome promote lung cancer initiation and development by modulating metabolic pathways, inhibiting the function of immune cells, and producing pro-inflammatory factors. In addition, some factors such as microbiota dysbiosis, affect production of bacteriotoxins, genotoxicity and virulence effect, therefore, they play a key role in cancer progression. These findings imply that lung and gut microbiome are potential markers and targets for lung cancer. However, the role of microbiota in development and progression of lung cancer has not been fully explored. Purpose The aim of this study was to systemically review recent research findings on relationship of lung and gut microbiota with lung cancer. In addition, we explored gut–lung axis and potential mechanisms of lung and gut microbiota in modulating lung cancer progression. Conclusion Pulmonary and intestinal flora influence the occurrence, development, treatment and prognosis of lung cancer, and will provide novel strategies for prevention, diagnosis, and treatment of lung cancer.

scholarly journals The Role of Cavin3 in the Progression of Lung Cancer and Its Mechanism

2020 ◽  
Vol 2020 ◽  
pp. 1-7
Author(s):  
Gaozhong Sun ◽  
Kewei Ni
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
Cancer Progression ◽  
Tumor Formation ◽  
Migration And Invasion ◽  
Clinical Value ◽  
Promote Cell Proliferation ◽  
Cancer Tissues

Objective. The purpose of this study was to describe the role of Cavin3 in the progression of lung cancer and its underlying mechanism. Methods. Totally, 200 cases of lung cancer tissues and corresponding paracancer tissues were collected. Cavin3 expression in samples was determined by qRT-PCR, and the correlation with lung cancer stages as well as prognosis was statistically analyzed combined with matched clinical information. To investigate the mechanism of Cavin3 in lung cancer progression, firstly, Cavin3 was detected in lung cancer cell lines A549, PC9, and H520. Then, cells with stable Cavin3 overexpression and Cavin3 knockout were established to determine the effect of Cavin3 overexpression on the mammalian target of rapamycin (mTOR) signaling pathway. Subsequently, cells were harvested for cell proliferation, migration, and invasion assays in vitro, as well as nude mouse transplantation tumor experiment in vivo. Results. Cavin3 was seen to be highly expressed in cancer tissues. Statistical analysis with matched clinical data showed that Cavin3 as a prognostic indicator of lung cancer had important clinical value. In addition, it could be found that high expression of Cavin3 was able to promote cell proliferation, migration, and invasion and also potentiate tumor formation in vivo. Conclusion. Cavin3 was highly expressed in lung cancer, and it was capable to promote cell proliferation, invasion, and migration.

AML Survival and In Vivo Progression Is Dependent On β-Catenin Signaling.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2398-2398
Author(s):  
Elena K Siapati ◽  
Magda Papadaki ◽  
Zoi Kozaou ◽  
Erasmia Rouka ◽  
Evridiki Michali ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Wnt Signaling ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Wnt Signaling Pathway ◽  
Canonical Wnt Signaling ◽  
Down Regulation ◽  
Canonical Wnt

Abstract Abstract 2398 Poster Board II-375 B-catenin is the central effector molecule of the canonical wnt signaling pathway which governs cell fate and differentiation during embryogenesis as well as self-renewal of hematopoietic stem cells. Deregulation of the pathway has been observed in various malignancies including myeloid leukemias where over-expression of β-catenin is an independent adverse prognostic factor. In the present study we examined the functional outcome of stable β-catenin down-regulation through lentivirus-mediated expression of short hairpin RNA (shRNA). Reduction of the β-catenin levels in AML cell lines and patient samples diminished their in vitro proliferation ability without significantly affecting cell viability. In order to study the role of β-catenin in vivo, we transplanted leukemic cell lines with control or reduced levels of β-catenin in NOD/SCID animals and analyzed the engraftment levels in the bone marrow. We observed that while the immediate homing of the cells was not affected by the β-catenin levels, the bone marrow engraftment was directly dependent on its levels. Subsequent examination of bone marrow sections revealed that the reduced engraftment was partly due to the inability of the cells with lower β-catenin levels to dock to the endosteal niches, a finding that was confirmed in competitive repopulation assays with untransduced cells. When we examined the expression levels of adhesion molecules and integrins in engrafted cells in vivo, we observed a significant down-regulation of CD44 expression, a molecule that participates in the interaction of HSCs with the niche. Gene expression analysis of the components of the wnt signaling pathway showed that the pathway is subject to tight transcriptional regulation with minor expression deviations. We did, however, observe an up-regulation in components that participate in the non-canonical wnt signaling pathways such as the WNT5B ligand. Ongoing experiments in normal cord blood CD34+ cells will determine the in vivo role of β-catenin signaling in normal hematopoietic progenitors. In conclusion, our study showed that β-catenin comprises an integral part in the development and progression of AML in vivo, indicating that manipulation of the wnt pathway may hold a therapeutic potential in the management of AML. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Treatment with the Recombinant SLIT2 Protein Delays AML Leukemogenesis In Vivo

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2368-2368
Author(s):  
Luise A de Albuquerque Simoes ◽  
Isabel Weinhäuser ◽  
Diego A Pereira-Martins ◽  
César Alexander Ortiz Rojas ◽  
Thiago Mantello Bianco ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Lines ◽  
Cancer Progression ◽  
Functional Role ◽  
Conflicts Of Interest ◽  
Therapeutic Potential ◽  
Leukemic Cells ◽  
Control Group

Abstract Accumulating evidence suggest that the axon guidance molecules SLIT and ROBO are not only implicated in physiological process but also in cancer progression. Depending on the type of cancer the SLIT-ROBO axis can either act as a tumor suppressor gene, in which case the SLIT2 promoter site is frequently hypermethylated or as an oncogene, whereby high expression is often associated with poor prognosis. In the context of acute myeloid leukemia (AML), low expression of SLIT2 has been associated with low overall survival (OS) (Golos et al., 2019), while the functional role of SLIT2 remains largely unknown. Recently, we showed that the knockdown of SLIT2 increased cell proliferation of acute promyelocytic leukemia (APL) cells resulting in a more aggressive course of disease progression in vivo using the murine transgenic APL model (Weinhäuser et al., 2020). Here, we aimed to study the functional role of SLIT2 in a more heterogeneous disease, such as AML. Using different publicly available datasets. (GSE58477, normal karyotype blasts: 62, healthy CD34 +: 10; GSE63409, LSC: 14, HSC: 5) we detected increased methylation at the SLIT2 promoter site of AML leukemic cells compared to healthy CD34 + cells suggesting SLIT2 tumor suppressive functions. In addition, we measured decreased levels of SLIT2 in the bone marrow (BM) plasma of AML patients compared to healthy donors. To assess the biological role of SLIT2, we treated AML cell lines (KASUMI1, MV411, and MOLM13) with recombinant SLIT2 (50 ng/mL) in vitro. Administration of SLIT2 reduced AML cell growth, colony formation and induced cell cycle arrest in the G1 phase for all AML cell lines. Conversely, the knockdown of SLIT2 promoted increased THP-1 and OCI-AML3 cell proliferation. Next, we determined whether the treatment with SLIT2 could delay leukemogenesis in vivo using the AML cell line MV4-11. Engraftment was monitored by luciferase bioluminescent signal and NSGS mice were either treated with recombinant SLIT2 using a dose of 25 ng/g of body weight or vehicle (control group). SLIT2 therapy resulted in a lower disease burden, decreased leukemic infiltration in the BM and spleen, reduced spleen size, and increased OS compared to the control group (p<0.05). In conclusion, we showed that SLIT2 methylation is recurrent in AML patients and that the level of SLIT2 in the plasma of AML patients is reduced. Moreover, SLIT2 treatment appears to have a cytostatic effect on different AML cell lines delaying leukemogenesis in vivo. Overall, our study reveals the therapeutic potential of SLIT2 in hematological malignancies, which could be used as an adjuvant in the clinic. Disclosures No relevant conflicts of interest to declare.

scholarly journals lncRNA OXCT1-AS1 Promotes Metastasis in Non-Small-Cell Lung Cancer by Stabilizing LEF1, In Vitro and In Vivo

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Binru Li ◽  
Libo Zhu ◽  
Linlin Li ◽  
Rui Ma
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lines ◽  
Small Cell ◽  
Small Cell Lung ◽  
Invasion And Migration ◽  
And Migration

Long noncoding RNAs (lncRNAs) play nonnegligible roles in the metastasis of non-small-cell lung cancer (NSCLC). This study is aimed at investigating the biological role of lncRNA OXCT1-AS1 in NSCLC metastasis and the underlying regulatory mechanisms. The expression profiles of lncRNA OXCT1-AS1 in different NSCLC cell lines were examined. Then, the biological function of lncRNA OXCT1-AS1 in NSCLC metastasis was explored by loss-of-function assays in vitro and in vivo. Further, the protective effect of lncRNA OXCT1-AS1 on lymphoid enhancer factor 1 (LEF1) was examined using RNA pull-down and RNA immunoprecipitation assays. Additionally, the role of LEF1 in NSCLC metastasis was investigated. Results indicated that lncRNA OXCT1-AS1 expression was significantly increased in NSCLC cell lines. Functional analysis revealed that knockdown of lncRNA OXCT1-AS1 impaired invasion and migration in vitro. Additionally, the ability of lncRNA OXCT1-AS1 to promote NSCLC metastasis was also confirmed in vivo. Mechanistically, through direct interaction, lncRNA OXCT1-AS1 maintained LEF1 stability by blocking NARF-mediated ubiquitination. Furthermore, LEF1 knockdown impaired invasion and migration of NSCLC in vitro and in vivo. Collectively, these data highlight the ability of lncRNA OXCT1-AS1 to promote NSCLC metastasis by stabilizing LEF1 and suggest that lncRNA OXCT1-AS1 represents a novel therapeutic target in NSCLC.

scholarly journals Circular RNA hsa_circ_0001829 promotes gastric cancer progression through miR-155-5p/SMAD2 axis

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Qiuling Niu ◽  
Zhijie Dong ◽  
Min Liang ◽  
Yuanwei Luo ◽  
Hai Lin ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Lines ◽  
Cancer Progression ◽  
Cell Cycle Progression ◽  
Luciferase Assay ◽  
Migration And Invasion ◽  
Circular Rnas ◽  
Gain Of Function

Abstract Background Accumulating evidences have shown that circular RNAs (circRNAs) play important roles in regulating the pathogenesis of cancer. However, the role of circRNAs in gastric cancer (GC) remains largely unclear. Methods In this study, we identified a novel upregulated circRNA, hsa_circ_0001829, in chemically induced malignant transformed human gastric epithelial cells using RNA-seq. Subsequent qRT-PCR and ISH assays were performed to detect the expression level of hsa_circ_0001829 in GC cell lines and tissues. Functional roles of hsa_circ_0001829 in GC were then explored by loss- and gain-of- function assays. Bioinformatic prediction and luciferase assay were used to investigate potential mechanisms of hsa_circ_0001829. Finally, the mice xenograft and metastasis models were constructed to assess the function of hsa_circ_0001829 in vivo. Results We found that hsa_circ_0001829 was significantly upregulated in GC tissues and cell lines. Loss- and gain-of- function assays showed that hsa_circ_0001829 promotes GC cells proliferation, migration and invasion, and the affected cell cycle progression and apoptosis rates may account for the effect of hsa_circ_0001829 on GC proliferation. In addition, bioinformatic prediction and luciferase assay showed that hsa_circ_0001829 acts as a molecular sponge for miR-155-5p and that SMAD2 was a target gene of miR-155-5p; moreover, hsa_circ_0001829 sponges miR-155-5p to regulate SMAD2 expression and hsa_circ_0001829 promotes GC progression through the miR-155-5p–SMAD2 pathway. Finally, suppression of hsa_circ_0001829 expression inhibited tumor growth and aggressiveness in vivo. Conclusion Taken together, our findings firstly demonstrated a novel oncogenic role of hsa_circ_0001829 in GC progression through miR-155-5p–SMAD2 axis, and our study may offer novel biomarkers and therapeutic targets for GC.

scholarly journals Circ_0044516 Regulates miR-136/MAT2A Pathway to Facilitate Lung Cancer Development

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Yue-Wei Chen ◽  
Qiu-Rong Du ◽  
Yu-Juan He ◽  
Wen-Shu Chen ◽  
Wen-Yang Jiang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
Cancer Progression ◽  
Noncoding Rna ◽  
Circular Rna ◽  
Vital Role ◽  
Migration And Invasion ◽  
Lung Cancer Patients

Circular RNA (circRNA) is a type of noncoding RNA that can interact with miRNAs to regulate gene expression. However, little is known concerning circRNA, which is crucial in the pathogenesis of lung cancer. To date, limited studies have explored the role of circ_0044516 in lung cancer progression. Recently, we observed that circ_0044516 expression levels were obviously elevated in lung cancer tissues and cells. A549 and SPCA1 cells were transfected with circ_0044516 siRNA. We observed that knockdown of circ_0044516 dramatically repressed cell proliferation, increased cell apoptosis, and repressed the cell cycle. Moreover, A549 and SPCA1 cell migration and invasion abilities were greatly repressed by circ_0044516 siRNA. Due to accumulating evidence demonstrating the vital role of cancer stem cells, their mechanism of involvement has drawn increasing attention in tumor progression and metastasis research. We also found that cancer stem cell properties were restrained by silencing circ_0044516 in A549 and SPC-A1 cells. Moreover, in vivo xenograft experiments showed that circ_0044516 downregulation reduced tumor growth. Mechanistically, in lung cancer and using bioinformatics, we demonstrated that circ_0044516 sponges miR-136 targeting MAT2A. Furthermore, rescue assays were carried out to identify that circ_0044516 modulates cell proliferation, invasion, and stemness by regulating miR-136 and MAT2A in lung cancer. In summary, our study revealed that the circ_0044516/miR-136/MAT2A axis is involved in lung cancer progression. Our findings may provide novel targets for diagnosis and therapeutic intervention in lung cancer patients.

scholarly journals A KRAS-responsive long non-coding RNA controls microRNA processing

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Lei Shi ◽  
Peter Magee ◽  
Matteo Fassan ◽  
Sudhakar Sahoo ◽  
Hui Sun Leong ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Progression ◽  
Lung Tumorigenesis ◽  
Downstream Signaling ◽  
Non Coding Rna ◽  
Microrna Processing ◽  
Long Non Coding Rna

AbstractWild-type KRAS (KRASWT) amplification has been shown to be a secondary means of KRAS activation in cancer and associated with poor survival. Nevertheless, the precise role of KRASWT overexpression in lung cancer progression is largely unexplored. Here, we identify and characterize a KRAS-responsive lncRNA, KIMAT1 (ENSG00000228709) and show that it correlates with KRAS levels both in cell lines and in lung cancer specimens. Mechanistically, KIMAT1 is a MYC target and drives lung tumorigenesis by promoting the processing of oncogenic microRNAs (miRNAs) through DHX9 and NPM1 stabilization while halting the biogenesis of miRNAs with tumor suppressor function via MYC-dependent silencing of p21, a component of the Microprocessor Complex. KIMAT1 knockdown suppresses not only KRAS expression but also KRAS downstream signaling, thereby arresting lung cancer growth in vitro and in vivo. Taken together, this study uncovers a role for KIMAT1 in maintaining a positive feedback loop that sustains KRAS signaling during lung cancer progression and provides a proof of principle that interfering with KIMAT1 could be a strategy to hamper KRAS-induced tumorigenesis.

Peruvoside is a new Src inhibitor that suppresses NSCLC cell growth and motility by downregulating multiple Src-EGFR-related pathways

2020 ◽  
Author(s):  
Yi-Hua Lai ◽  
Hsiu-Hui Chang ◽  
Huei-Wen Chen ◽  
Gee-Chen Chang ◽  
Jeremy JW Chen
Keyword(s):  
Lung Cancer ◽  
Protein Expression ◽  
Small Cell Lung Cancer ◽  
Cell Lines ◽  
Cancer Progression ◽  
Cell Function ◽  
Synergistic Effects ◽  
Small Cell ◽  
Small Cell Lung

Abstract Background The tyrosine kinase Src plays an essential role in the progression of many cancers and is involved in several signalling pathways regulated by EGFR. To improve the efficacy of lung cancer treatments, this study aimed to identify novel compounds that can disrupt the Src-EGFR interaction to inhibit lung cancer progression and are less dependent on the EGFR mutation status than other compounds. Methods We used Src pY419 ELISA as the drug-screening platform to screen a compound library of more than 400 plant active ingredients and identified peruvoside as a candidate Src-EGFR crosstalk inhibitor. Human Non-small cell lung cancer cell lines (A549, PC9, PC9/gef, H3255 and H1975) with different EGFR statuses were used to perform cell cytotoxicity and proliferation assays after peruvoside or dasatinib treatment. Src and Src-related protein expression was evaluated by western blotting in peruvoside-treated A549, H3255 and H1975 cells. The effects of peruvoside on cancer cell function were assessed in A549 cells. The synergistic effects of gefitinib and peruvoside were assessed by CI-isobologram analysis in gefitinib-resistant cell lines. The efficacy of peruvoside in vivo was determined using nude mice subjected to compound or vehicle treatments. Results Peruvoside significantly suppressed the phosphorylation of Src, EGFR, and STAT3 in a dose- and time-dependent manner and somewhat suppressed their protein expression. Cell function assays revealed that peruvoside also inhibited the proliferation, invasion, migration, and colony formation of lung cancer cells in vitro and tumour growth in vivo. Furthermore, peruvoside sensitised gefitinib-resistant tumour cells (A549, PC9/gef and H1975) to gefitinib treatment, indicating that it may exert synergistic effects when used in combination with established therapeutic agents. Our data also demonstrated that the inhibitory effects of peruvoside on lung cancer progression might be attributed to its ability to regulate multiple proteins, including Src, PI3K, JNK, Paxillin, p130cas, and EGFR. Conclusions Our findings suggest that peruvoside suppresses Non-small cell lung cancer malignancy by downregulating multiple Src-related pathways and may help develop new anticancer drugs and therapeutic strategies for lung cancer in the future.

scholarly journals LINC01342 silencing upregulates microRNA-508-5p to inhibit progression of lung cancer by reducing cysteine-rich secretory protein 3

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Qiming Shen ◽  
Zhe Xu ◽  
Guanghao Sun ◽  
Haoyou Wang ◽  
Lin Zhang
Keyword(s):  
Lung Cancer ◽  
Tumor Growth ◽  
Cancer Progression ◽  
Noncoding Rnas ◽  
Secretory Protein ◽  
Migration And Invasion ◽  
Clinical Samples ◽  
Prognostic Role

AbstractLong noncoding RNAs (lncRNAs) are critical players during cancer progression. Nevertheless, the effect of most lncRNAs in lung cancer (LC) remains unclear. We aimed to explore the role of LINC01342 in LC development through the microRNA-508-5p (miR-508-5p)/cysteine-rich secretory protein 3 (CRISP3) axis. LINC01342, miR-508-5p, and CRISP3 expression in clinical samples and cell lines were determined, and their correlations in LC were analyzed. The prognostic role of LINC01342 in LC patients was evaluated. LC cells were screened and, respectively, transfected to alter the expression of LINC01342, miR-508-5p, and CRISP3. Then, proliferation, migration, invasion, and apoptosis of transfected LC cells were determined, and the in vivo tumor growth was observed as well. Binding relationships between LINC01342 and miR-508-5p, and between miR-508-5p and CRISP3 were identified. LINC01342 and CRISP3 were upregulated and miR-508-5p was downregulated in LC tissues and cells. High LINC01342 expression indicated a poor prognosis of LC patients. The LINC01342/CRISP3 silencing or miR-508-5p elevation inhibited proliferation, migration, and invasion of LC cells and promoted LC cell apoptosis, and also suppressed the in vivo tumor growth. LINC01342 bound to miR-508-5p and miR-508-5p targeted CRISP3. LINC01342 plays a prognostic role in LC and LINC01342 silencing upregulates miR-508-5p to inhibit the progression of LC by reducing CRISP3.

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