scholarly journals LncRNA FAM83H-AS1 Amplification is Associated With a Poor Prognosis in Lung Adenocarcinoma and Can Serve as A Therapeutic Target

2020 ◽  
Author(s):  
Siwei Wang ◽  
Chencheng Han ◽  
Tongyan Liu ◽  
Zhifei Ma ◽  
Mantang Qiu ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Poor Prognosis ◽  
Therapeutic Potential ◽  
Gene Annotation ◽  
Tumor Xenograft ◽  
Driver Gene ◽  
Clinical Prognosis ◽  
Crispr Interference ◽  
Oncogenic Driver

Abstract Background: Few oncogenic drivers of long noncoding RNAs (lncRNAs) have been identified and investigated. Identifying noncoding drivers provides potential strategies for novel interventions in lung adenocarcinoma (LUAD). Methods: We constructed a machine learning model for driver gene annotation using pan-cancer and clinical prognosis data from OncoKB and TCGA to predict potential oncogenic drivers of lncRNAs; then, we used zebrafish models to validate the biological function of candidate targets. The full length of FAM83H-AS1 was obtained by rapid amplification of the cDNA ends (RACE) assay. RNA pull-down, RNA immunoprecipitation (RIP), quantative mass spectrometry (QMS) and RNA sequencing (RNA-Seq) assays were utilized to explore the potential mechanisms. Additionally, we used CRISPR interference (CRISPRi) system and patient-derived tumor xenograft (PDTX) model to evaluate the therapeutic potential of targeting FAM83H-AS1 in vivo.Results: The results suggested that FAM83H-AS1 was a potential oncogenic driver from the chromosome 8q24 amplicon; increases in the expression of FAM83H-AS1 resulted in poor prognosis for LUAD patients both in JSCH and TCGA cohorts. Functional assays revealed that FAM83H-AS1 promotes malignant progression and inhibits apoptosis. Mechanistically, FAM83H-AS1 binds with HNRNPK to enhance the translation of oncogenes RAB8B and RAB14. Experiments using CRISPR interference (CRISPRi)-mediated xenografts and patient-derived tumor xenograft (PDTX) models indicated that targeting FAM83H-AS1 inhibited LUAD progression in vivo. Conclusions: Our work demonstrated that FAM83H-AS1 is a potential oncogenic driver that inhibits LUAD-mediated apoptosis via the FAM83H-AS1-HNRNPK-RAB8B/RAB14 axis. Importantly, we suggest targeting of FAM83H-AS1 as a potential therapeutic strategy for LUAD.

scholarly journals Requirement for PKC Epsilon in Kras-Driven Lung Tumorigenesis

2020 ◽  
Author(s):  
Rachana Garg ◽  
Mariana Cooke ◽  
Shaofei Wang ◽  
Fernando Benavides ◽  
Martin C. Abba ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Cancer Therapeutics ◽  
Rna Seq ◽  
Lung Tumorigenesis ◽  
Mechanistic Analysis ◽  
Oncogenic Driver ◽  
Histological Form

ABSTRACTNon-small cell lung cancer (NSCLC), the most frequent subtype of lung cancer, remains a highly lethal malignancy and one of the leading causes of cancer deaths worldwide. Mutant KRAS is the prevailing oncogenic driver of lung adenocarcinoma, the most common histological form of NSCLC. In this study, we examined the role of PKCε, an oncogenic kinase highly expressed in NSCLC and other cancers, in KRAS-driven tumorigenesis. Notably, database analysis revealed an association between PKCε expression and poor outcome in lung adenocarcinoma patients specifically having KRAS mutation. By generating a PKCε-deficient, conditionally activatable allele of oncogenic Kras (LSL-KrasG12D;PKCε−/− mice) we were able to demonstrate the requirement of PKCε for Kras-driven lung tumorigenesis in vivo, which is consistent with the impaired transformed growth observed in PKCε-deficient KRAS-dependent NSCLC cells. Moreover, PKCε-knockout mice were found to be less susceptible to lung tumorigenesis induced by benzo[a]pyrene, a carcinogen that induces mutations in Kras. Mechanistic analysis using RNA-Seq revealed little overlapping for PKCε and KRAS in the control of genes/biological pathways relevant in NSCLC, suggesting that a permissive role of PKCε in KRAS-driven lung tumorigenesis may involve non-redundant mechanisms. Our results thus highlight the relevance and potential of targeting PKCε for lung cancer therapeutics.

scholarly journals The SARS-CoV-2 Host Cell Membrane Fusion Protein TMPRSS2 is A Tumor Suppressor and its Downregulation Promotes Antitumor Immunity and Immunotherapy Response in Lung Adenocarcinoma

2021 ◽  
Author(s):  
Zhixian Liu ◽  
Zhilan Zhang ◽  
Qiushi Feng ◽  
Xiao-Sheng Wang
Keyword(s):  
Lung Cancer ◽  
Tumor Suppressor ◽  
Lung Adenocarcinoma ◽  
Tumor Progression ◽  
Antitumor Immunity ◽  
Host Cells ◽  
Host Cell Membrane ◽  
Clinical Prognosis ◽  
In Vivo Experiments

Abstract TMPRSS2, a key molecule for SARS-CoV-2 invading human host cells, has an association with cancer. However, its association with lung cancer remains unexplored. In five lung adenocarcinoma (LUAD) genomics datasets, we explored associations between TMPRSS2 expression and immune signatures, tumor progression phenotypes, and clinical prognosis in LUAD by the bioinformatics approach. We found that TMPRSS2 expression levels correlated negatively with the enrichment levels of both immune-stimulatory and immune-inhibitory signatures, while they correlated positively with the ratios of immune-stimulatory/immune-inhibitory signatures. It indicated that TMPRSS2 levels had a stronger negative correlation with immune-inhibitory than with immune-stimulatory signatures. TMPRSS2 downregulation correlated with increased proliferation, stemness, genomic instability, tumor progression, and worse survival in LUAD. We further validated that TMPRSS2 was downregulated with tumor progression in the LUAD dataset we collected. In vitro and in vivo experiments verified the association of TMPRSS2 deficiency with increased tumor cell proliferation and invasion and antitumor immunity in LUAD. Moreover, in vivo experiments demonstrated that TMPRSS2-knockdown tumors were more sensitive to BMS-1, an inhibitor of PD-1/PD-L1. In conclusion, TMPRSS2 is a tumor suppressor, while its downregulation is a positive biomarker of immunotherapy in LUAD. Our data provide a link between lung cancer and pneumonia caused by SARS-CoV-2 infection.

R-spondin3 promotes the tumor growth of choriocarcinoma JEG-3 cells

2020 ◽  
Vol 318 (3) ◽  
pp. C664-C674
Author(s):  
Zhilong Chen ◽  
Juzuo Zhang ◽  
Anwen Yuan ◽  
Jinyu Han ◽  
Lunbo Tan ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Soft Agar ◽  
Tumor Xenograft ◽  
Nuclear Antigen ◽  
Phosphatidylinositol 3 Kinase ◽  
Human Term Placenta ◽  
Term Placenta ◽  
Oncogenic Driver

R-spondin3 (RSPO3), an activator of Wnt/β-catenin signaling, plays a key role in tumorigenesis of various cancers, but its role in choriocarcinoma remains unknown. To investigate the effect of RSPO3 on the tumor growth of choriocarcinoma JEG-3 cells, the expression of RSPO3 in human term placenta was detected, and a stable RSPO3-overexpressing JEG-3 cell line was established via lentivirus-mediated transduction. The expression of biomarkers involved in tumorigenicity was detected in the RSPO3-overexpressing JEG-3 cells, and cell proliferation, invasion, migration, and apoptosis were investigated. Moreover, soft agar clonogenic assays and xenograft tumorigenicity assays were performed to assess the effect of RSPO3 on tumor growth in vitro and in vivo. The results showed that RSPO3 was widely expressed in human term placenta and overexpression of RSPO3 promoted the proliferation and inhibited the migration, invasion, and apoptosis of the JEG-3 cells. Meanwhile, RSPO3 overexpression promoted tumor growth both in vivo and in vitro. Further investigation showed that the phosphorylation levels of Akt, phosphatidylinositol 3-kinase (PI3K), and ERK as well the expression of β-catenin and proliferating cell nuclear antigen (PCNA) were increased in the RSPO3-overexpressing JEG-3 cells and tumor xenograft. Taken together, these data indicate that RSPO3 promotes the tumor growth of choriocarcinoma via Akt/PI3K/ERK signaling, which supports RSPO3 as an oncogenic driver promoting the progression of choriocarcinoma.

A novel polypeptide from Meretrix meretrix Linnaeus inhibits the growth of human lung adenocarcinoma

2012 ◽  
Vol 237 (4) ◽  
pp. 442-450 ◽  
Author(s):  
Cuicui Wang ◽  
Ming Liu ◽  
Linyou Cheng ◽  
Jianteng Wei ◽  
Ning Wu ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Human Lung ◽  
Therapeutic Potential ◽  
Human Cancer ◽  
Small Cell Lung Carcinoma ◽  
Reversed Phase ◽  
Meretrix Meretrix ◽  
Cell Lung Carcinoma ◽  
Human Lung Adenocarcinoma

A novel polypeptide (Mere15) was purified from Meretrix meretrix Linnaeus by ammonium sulfate fractionation, ion exchange, gel filtration and reversed phase chromatography. Mere15 exhibited selective cytotoxicity to several human cancer cells. In vivo study showed that Mere15 significantly suppressed the growth of human lung adenocarcinoma A549 xenograft in nude mice. The mechanism was associated with a G2/M phase arrest followed by apoptosis, including membrane blebbing, loss of mitochondrial membrane potential, externalization of phosphatidylserine, chromosome condensation and DNA fragmentation. Western blot analysis showed that the intrinsic pathway was involved in Mere15-induced apoptosis. These results suggest that Mere15 may have therapeutic potential for the treatment of non-small-cell lung carcinoma.

scholarly journals Connexin 43 confers chemoresistance through activating PI3K

Oncogenesis ◽  
2022 ◽  
Vol 11 (1) ◽  
Author(s):  
Kevin J. Pridham ◽  
Farah Shah ◽  
Kasen R. Hutchings ◽  
Kevin L. Sheng ◽  
Sujuan Guo ◽  
...  
Keyword(s):  
Poor Prognosis ◽  
Connexin 43 ◽  
Therapeutic Potential ◽  
Mrna Levels ◽  
Phosphatidylinositol 3 Kinase ◽  
Junction Protein ◽  
Gap Junction Protein ◽  
Cx43 Mrna

AbstractCircumventing chemoresistance is crucial for effectively treating cancer including glioblastoma, a lethal brain cancer. The gap junction protein connexin 43 (Cx43) renders glioblastoma resistant to chemotherapy; however, targeting Cx43 is difficult because mechanisms underlying Cx43-mediated chemoresistance remain elusive. Here we report that Cx43, but not other connexins, is highly expressed in a subpopulation of glioblastoma and Cx43 mRNA levels strongly correlate with poor prognosis and chemoresistance in this population, making Cx43 the prime therapeutic target among all connexins. Depleting Cx43 or treating cells with αCT1–a Cx43 peptide inhibitor that sensitizes glioblastoma to the chemotherapy temozolomide–inactivates phosphatidylinositol-3 kinase (PI3K), whereas overexpression of Cx43 activates this signaling. Moreover, αCT1-induced chemo-sensitization is counteracted by a PI3K active mutant. Further research reveals that αCT1 inactivates PI3K without blocking the release of PI3K-activating molecules from membrane channels and that Cx43 selectively binds to the PI3K catalytic subunit β (PIK3CB, also called PI3Kβ or p110β), suggesting that Cx43 activates PIK3CB/p110β independent of its channel functions. To explore the therapeutic potential of simultaneously targeting Cx43 and PIK3CB/p110β, αCT1 is combined with TGX-221 or GSK2636771, two PIK3CB/p110β-selective inhibitors. These two different treatments synergistically inactivate PI3K and sensitize glioblastoma cells to temozolomide in vitro and in vivo. Our study has revealed novel mechanistic insights into Cx43/PI3K-mediated temozolomide resistance in glioblastoma and demonstrated that targeting Cx43 and PIK3CB/p110β together is an effective therapeutic approach for overcoming chemoresistance.

scholarly journals Overexpression of Long Non-Coding RNA NNT-AS1 Correlates with Tumor Progression and Poor Prognosis in Osteosarcoma

2018 ◽  
Vol 45 (5) ◽  
pp. 1904-1914 ◽  
Author(s):  
Hui Ye ◽  
Jinkuang Lin ◽  
Xuedong Yao ◽  
Yizhong Li ◽  
Xiaobin Lin ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Poor Prognosis ◽  
Significant Risk ◽  
Xenograft Model ◽  
Significant Risk Factor ◽  
Tumor Xenograft ◽  
Migration And Invasion ◽  
Mouse Xenograft Model

Background/Aims: Increasing evidence demonstrates that long non-coding RNAs (lncRNAs) play critical regulatory roles in cancers, including osteosarcoma. A previous study showed that Nicotinamide Nucleotide Transhydrogenase-antisense RNA1 (NNT-AS1) was aberrantly expressed in several types of cancer. However, the potential biological roles and regulatory mechanisms of NNT-AS1 in osteosarcoma progression remain unknown. Methods: Quantitative RT-PCR was performed to examine the expression of NNT-AS1 in human tissues and cells. The biological functions of NNT-AS1 were determined by CCK-8, colony formation, Flow cytometry and Transwell assays in vitro. A mouse xenograft model was performed to investigate the effect of NNT-AS1 on tumor growth in vivo. Results: In this study, we found the expression of NNT-AS1 was significantly increased in tumor tissues compared to adjacent normal tissues. Furthermore, upregulated NNT-AS1 expression predicted poor prognosis and was an independent and significant risk factor for osteosarcoma patient survival. Further experiments revealed that NNT-AS1 knockdown significantly inhibited cell proliferation by inducing cell cycle arrest and promoting apoptosis in osteosarcoma cells. Moreover, NNT-AS1 silencing suppressed cell migration and invasion in vitro. In a tumor xenograft model, knockdown of NNT-AS1 suppressed tumor growth of OS-732 cells in vivo. Conclusions: Taken together, these findings indicate that NNT-AS1 functions as an oncogene in osteosarcoma and could be a novel diagnostic and therapeutic target for osteosarcoma.

scholarly journals CDK5RAP3 inhibits angiogenesis in gastric neuroendocrine carcinoma by modulating AKT/HIF-1α/VEGFA signaling

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Jian-Xian Lin ◽  
Xiong-Feng Weng ◽  
Xin-Sheng Xie ◽  
Ning-Zi Lian ◽  
Sheng-Liang Qiu ◽  
...  
Keyword(s):  
Neuroendocrine Carcinoma ◽  
Poor Prognosis ◽  
Malignant Tumors ◽  
Umbilical Vein ◽  
Tube Formation ◽  
Tumor Xenograft ◽  
Biological Behavior ◽  
Tumor Tissues ◽  
Gastric Neuroendocrine Carcinoma

Abstract Background Angiogenesis plays critical roles in the progression and metastasis of malignant tumors. Gastric neuroendocrine carcinoma is an uncommon stomach cancer that is rich in blood vessels and exhibits highly malignant biological behavior with a poor prognosis. The role of CDK5RAP3 in GNEC has not been reported to date. Methods Immunohistochemistry was used to assess the expression of CDK5RAP3 in GNEC tissues and adjacent non-tumor tissues. Cell lines with stable overexpression or knockdown of CDK5RAP3 were constructed using lentiviral transfection. Wound-healing assays, invasion and metastasis assays, tube formation assays, and tumor xenograft transplantation assays were performed to evaluate the effect of CDK5RAP3 on GNEC angiogenesis in vitro and in vivo. Real-time PCR, ELISA, western blot analysis, and confocal-immunofluorescence staining were used to explore the molecular mechanism of CDK5RAP3′s effect on angiogenesis. Results Compared with their respective adjacent non-tumor tissues, protein levels of CDK5RAP3 were significantly decreased in GNEC tissues. Furthermore, low expression of CDK5RAP3 was correlated with more advanced TNM stage, increased tumor microvessel density, and poor prognosis. Functionally, we found that GNEC cells with CDK5RAP3 knockdown promoted human umbilical vein endothelial cells migration and tube formation via activation of AKT/HIF-1α/VEGFA signaling, resulting in increased levels of VEGFA in GNEC cell supernatant. In addition, CDK5RAP3 overexpression in GNEC cells caused the opposing effect. Consistent with these results, nude mouse tumorigenicity assays showed that CDK5RAP3 expression downregulated angiogenesis in vivo. Lastly, patients with low CDK5RAP3 expression and high VEGFA expression exhibited the worst prognosis. Conclusions This study demonstrated that CDK5RAP3 inhibits angiogenesis by downregulating AKT/HIF-1α/VEGFA signaling in GNEC and improves patient prognosis, suggesting that CDK5RAP3 could be a potential therapeutic target for GNEC.

scholarly journals Therapeutic Potential of EWSR1–FLI1 Inactivation by CRISPR/Cas9 in Ewing Sarcoma

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3783
Author(s):  
Saint T. Cervera ◽  
Carlos Rodríguez-Martín ◽  
Enrique Fernández-Tabanera ◽  
Raquel M. Melero-Fernández de Mera ◽  
Matias Morin ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Ewing Sarcoma ◽  
Therapeutic Potential ◽  
Bone Cancer ◽  
Genetic Inactivation ◽  
Complete Inactivation ◽  
Oncogenic Driver ◽  
Sarcoma Cells ◽  
Block Cell Proliferation

Ewing sarcoma is an aggressive bone cancer affecting children and young adults. The main molecular hallmark of Ewing sarcoma are chromosomal translocations that produce chimeric oncogenic transcription factors, the most frequent of which is the aberrant transcription factor EWSR1–FLI1. Because this is the principal oncogenic driver of Ewing sarcoma, its inactivation should be the best therapeutic strategy to block tumor growth. In this study, we genetically inactivated EWSR1–FLI1 using CRISPR-Cas9 technology in order to cause permanent gene inactivation. We found that gene editing at the exon 9 of FLI1 was able to block cell proliferation drastically and induce senescence massively in the well-studied Ewing sarcoma cell line A673. In comparison with an extensively used cellular model of EWSR1–FLI1 knockdown (A673/TR/shEF), genetic inactivation was more effective, particularly in its capability to block cell proliferation. In summary, genetic inactivation of EWSR1–FLI1 in A673 Ewing sarcoma cells blocks cell proliferation and induces a senescence phenotype that could be exploited therapeutically. Although efficient and specific in vivo CRISPR-Cas9 editing still presents many challenges today, our data suggest that complete inactivation of EWSR1–FLI1 at the cell level should be considered a therapeutic approach to develop in the future.

scholarly journals β-Trcp and CK1δ-mediated degradation of LZTS2 activates PI3K/AKT signaling to drive tumorigenesis and metastasis in hepatocellular carcinoma

Oncogene ◽  
2021 ◽  
Author(s):  
Yanwei Lu ◽  
Xudong Li ◽  
Hongli Liu ◽  
Jun Xue ◽  
Zhen Zeng ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Posttranslational Modification ◽  
Poor Prognosis ◽  
Leucine Zipper ◽  
Akt Signaling ◽  
Bona Fide ◽  
Oncogenic Driver ◽  
Underlying Mechanisms

AbstractDistant metastasis is the leading cause of treatment failure in patients with hepatocellular carcinoma (HCC). However, the underlying mechanisms have not been fully elucidated. Here, we report that Leucine zipper tumor suppressor 2 (LZTS2) is downregulated and correlated with poor prognosis in HCC. Furthermore, we provide evidence that LZTS2 associates with p85 to inhibit the activation of PI3K/AKT signaling and impairs HCC tumorigenesis and metastasis in vitro and in vivo. Moreover, we identify LZTS2 as a bona fide substrate of the E3 ligase β-Trcp and protein kinase CK1δ, which are responsible for the ubiquitination and degradation of LZTS2. Importantly, we show that the β-Trcp and CK1δ-mediated degradation of LZTS2 promotes HCC progression and metastasis by activating PI3K/AKT signaling. Collectively, our study not only illustrates the roles of LZTS2 in regulating HCC tumorigenesis and metastasis but also reveals a novel posttranslational modification of LZTS2 by β-Trcp and CK1δ, indicating that the β-Trcp/CK1δ/LZTS2/PI3K axis may be a novel oncogenic driver involved in HCC progression and metastasis.

scholarly journals Inhibition of TMEM16A by Natural Product Silibinin: Potential Lead Compounds for Treatment of Lung Adenocarcinoma

2021 ◽  
Vol 12 ◽  
Author(s):  
Shuai Guo ◽  
Xue Bai ◽  
Yufei Liu ◽  
Sai Shi ◽  
Xuzhao Wang ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Binding Sites ◽  
Drug Targets ◽  
Inhibitory Effect ◽  
New Drugs ◽  
Site Directed Mutagenesis ◽  
Tumor Xenograft ◽  
Whole Cell ◽  
Xenograft Mice

Background: Effective anticancer therapy can be achieved by identifying novel tumor-specific drug targets and screening of new drugs. Recently, TMEM16A has been identified to be overexpressed in lung adenocarcinoma, and inhibitors of TMEM16A showed obvious antitumor efficacy.Methods: YFP fluorescence quenching and whole-cell patch clamp experiments were used to explore the inhibitory effect of silibinin on TMEM16A. Molecular docking and site-directed mutagenesis were performed to confirm the binding sites of silibinin and TMEM16A. MTT assay, wound healing assay, and annexin-V assay were used to detect the effect of silibinin on cancer cell proliferation, migration, and apoptosis. shRNA was transfected into LA795 cells to knock down the expression of endogenous TMEM16A. Tumor xenograft mice combined with Western blot experiments reveal the inhibitory effect and mechanism of silibinin in vivo.Results: Silibinin concentration dependently inhibited the whole-cell current of TMEM16A with an IC50 of 30.90 ± 2.10 μM. The putative binding sites of silibinin in TMEM16A were K384, R515, and R535. The proliferation and migration of LA795 cells were downregulated by silibinin, and the inhibition effect can be abolished by knockdown of the endogenous TMEM16A. Further, silibinin was injected to tumor xenograft mice which exhibited significant antitumor activity without weight loss. Finally, Western blotting results showed the mechanism of silibinin inhibiting lung adenocarcinoma was through apoptosis and downregulation of cyclin D1.Conclusion: Silibinin is a novel TMEM16A inhibitor, and it can be used as a lead compound for the development of lung adenocarcinoma therapy drugs.

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