Requirement for PKC Epsilon in Kras-Driven Lung Tumorigenesis

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.

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Targeting HSPA1A in ARID2-deficient lung adenocarcinoma

National Science Review ◽

10.1093/nsr/nwab014 ◽

2021 ◽

Author(s):

Xue Wang ◽

Yuetong Wang ◽

Zhaoyuan Fang ◽

Hua Wang ◽

Jian Zhang ◽

...

Keyword(s):

Lung Cancer ◽

Lung Adenocarcinoma ◽

Genetically Engineered ◽

Malignant Progression ◽

Murine Models ◽

Rna Seq ◽

Potential Therapeutic Target ◽

Lung Cancers ◽

Integrative Analyses

Abstract Somatic mutations of the chromatin remodeling gene ARID2 are observed in about 7% of human lung adenocarcinoma (LUAD). However, the role of ARID2 in the pathogenesis of LUAD remains largely unknown. Here we find that ARID2 expression is decreased during the malignant progression of both human and mice LUAD. Using two KrasG12D-based genetically engineered murine models (GEMM), we demonstrate that ARID2 knockout significantly promotes lung cancer malignant progression and shortens the overall survival. Consistently, ARID2 knockdown significantly promotes cell proliferation in human and mice lung cancer cells. Through integrative analyses of Chip-Seq and RNA-Seq data, we find that Hspa1a is up-regulated by Arid2 loss. Knockdown of Hspa1a specifically inhibits malignant progression of Arid2-deficient but not Arid2-wt lung cancers in both cell lines as well as animal models. Treatment with Hspa1a inhibitor could significantly inhibit the malignant progression of lung cancer with Arid2 deficiency. Together, our findings establish ARID2 as an important tumor suppressor in LUAD with novel mechanistic insights, and further identify HSPA1A as a potential therapeutic target in ARID2-deficient LUAD.

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Role of race in oncogenic driver prevalence and outcomes in lung adenocarcinoma: Results from the Lung Cancer Mutation Consortium

Cancer ◽

10.1002/cncr.29812 ◽

2015 ◽

Vol 122 (5) ◽

pp. 766-772 ◽

Cited By ~ 30

Author(s):

Conor E. Steuer ◽

Madhusmita Behera ◽

Lynne Berry ◽

Sungjin Kim ◽

Michael Rossi ◽

...

Keyword(s):

Lung Cancer ◽

Lung Adenocarcinoma ◽

Cancer Mutation ◽

Oncogenic Driver

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

Nature Communications ◽

10.1038/s41467-021-22337-3 ◽

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.

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PPM1G promotes the progression of hepatocellular carcinoma via phosphorylation regulation of alternative splicing protein SRSF3

Cell Death and Disease ◽

10.1038/s41419-021-04013-y ◽

2021 ◽

Vol 12 (8) ◽

Author(s):

Dawei Chen ◽

Zhenguo Zhao ◽

Lu Chen ◽

Qinghua Li ◽

Jixue Zou ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Alternative Splicing ◽

Protein Function ◽

Vital Role ◽

Normal Tissues ◽

Mechanistic Analysis ◽

Highly Correlated ◽

Splicing Patterns

AbstractEmerging evidence has demonstrated that alternative splicing has a vital role in regulating protein function, but how alternative splicing factors can be regulated remains unclear. We showed that the PPM1G, a protein phosphatase, regulated the phosphorylation of SRSF3 in hepatocellular carcinoma (HCC) and contributed to the proliferation, invasion, and metastasis of HCC. PPM1G was highly expressed in HCC tissues compared to adjacent normal tissues, and higher levels of PPM1G were observed in adverse staged HCCs. The higher levels of PPM1G were highly correlated with poor prognosis, which was further validated in the TCGA cohort. The knockdown of PPM1G inhibited the cell growth and invasion of HCC cell lines. Further studies showed that the knockdown of PPM1G inhibited tumor growth in vivo. The mechanistic analysis showed that the PPM1G interacted with proteins related to alternative splicing, including SRSF3. Overexpression of PPM1G promoted the dephosphorylation of SRSF3 and changed the alternative splicing patterns of genes related to the cell cycle, the transcriptional regulation in HCC cells. In addition, we also demonstrated that the promoter of PPM1G was activated by multiple transcription factors and co-activators, including MYC/MAX and EP300, MED1, and ELF1. Our study highlighted the essential role of PPM1G in HCC and shed new light on unveiling the regulation of alternative splicing in malignant transformation.

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Kras-driven intratumoral heterogeneity triggers infiltration of M2 polarized macrophages via the circHIPK3/PTK2 immunosuppressive circuit

Scientific Reports ◽

10.1038/s41598-021-94671-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Theodora Katopodi ◽

Savvas Petanidis ◽

Kalliopi Domvri ◽

Paul Zarogoulidis ◽

Doxakis Anestakis ◽

...

Keyword(s):

Lung Cancer ◽

Tumor Growth ◽

Lung Tumor ◽

Quantitative Polymerase Chain Reaction ◽

Macrophage Polarization ◽

Metastatic Potential ◽

Intratumoral Heterogeneity ◽

M2 Macrophage

AbstractIntratumoral heterogeneity in lung cancer is essential for evasion of immune surveillance by tumor cells and establishment of immunosuppression. Gathering data reveal that circular RNAs (circRNAs), play a role in the pathogenesis and progression of lung cancer. Particularly Kras-driven circRNA signaling triggers infiltration of myeloid-associated tumor macrophages in lung tumor microenvironment thus establishing immune deregulation, and immunosuppression but the exact pathogenic mechanism is still unknown. In this study, we investigate the role of oncogenic Kras signaling in circRNA-related immunosuppression and its involvement in tumoral chemoresistance. The expression pattern of circRNAs HIPK3 and PTK2 was determined using quantitative polymerase chain reaction (qPCR) in lung cancer patient samples and cell lines. Apoptosis was analyzed by Annexin V/PI staining and FACS detection. M2 macrophage polarization and MDSC subset analysis (Gr1−/CD11b−, Gr1−/CD11b+) were determined by flow cytometry. Tumor growth and metastatic potential were determined in vivo in C57BL/6 mice. Findings reveal intra-epithelial CD163+/CD206+ M2 macrophages to drive Kras immunosuppressive chemoresistance through myeloid differentiation. In particular, monocytic MDSC subsets Gr1−/CD11b−, Gr1−/CD11b+ triggered an M2-dependent immune response, creating an immunosuppressive tumor-promoting network via circHIPK3/PTK2 enrichment. Specifically, upregulation of exosomal cicHIPK3/PTK2 expression prompted Kras-driven intratumoral heterogeneity and guided lymph node metastasis in C57BL/6 mice. Consequent co-inhibition of circPTK2/M2 macrophage signaling suppressed lung tumor growth along with metastatic potential and prolonged survival in vivo. Taken together, these results demonstrate the key role of myeloid-associated macrophages in sustaining lung immunosuppressive neoplasia through circRNA regulation and represent a potential therapeutic target for clinical intervention in metastatic lung cancer.

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

10.21203/rs.3.rs-45692/v1 ◽

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.

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The role of the NMD factor UPF3B in olfactory sensory neurons

eLife ◽

10.7554/elife.57525 ◽

2020 ◽

Vol 9 ◽

Cited By ~ 1

Author(s):

Kun Tan ◽

Samantha H Jones ◽

Blue B Lake ◽

Jennifer N Dumdie ◽

Eleen Y Shum ◽

...

Keyword(s):

Human Cognition ◽

Cell Populations ◽

Rna Seq ◽

Wild Type ◽

Single Cell Rna Sequencing ◽

Nonsense Mediated Rna Decay ◽

Different Levels ◽

Selection Of

The UPF3B-dependent branch of the nonsense-mediated RNA decay (NMD) pathway is critical for human cognition. Here, we examined the role of UPF3B in the olfactory system. Single-cell RNA-sequencing (scRNA-seq) analysis demonstrated considerable heterogeneity of olfactory sensory neuron (OSN) cell populations in wild-type (WT) mice, and revealed that UPF3B loss influences specific subsets of these cell populations. UPF3B also regulates the expression of a large cadre of antimicrobial genes in OSNs, and promotes the selection of specific olfactory receptor (Olfr) genes for expression in mature OSNs (mOSNs). RNA-seq and Ribotag analyses identified classes of mRNAs expressed and translated at different levels in WT and Upf3b-null mOSNs. Integrating multiple computational approaches, UPF3B-dependent NMD target transcripts that are candidates to mediate the functions of NMD in mOSNs were identified in vivo. Together, our data provides a valuable resource for the olfactory field and insights into the roles of NMD in vivo.

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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

10.21203/rs.3.rs-740479/v2 ◽

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.

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Transthyretin (TTR) Suppressed Tumor Progression in Non-Small Cell Lung Cancer by Inactivating MAPK/ERK Pathway

10.21203/rs.3.rs-38779/v1 ◽

2020 ◽

Author(s):

Dong-bin Wang ◽

Xuan Li ◽

Xi-ke Lu ◽

Zhong-yi Sun ◽

Xun Zhang ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Carcinoma ◽

Clinical Care ◽

Small Cell ◽

Signal Pathways ◽

Small Cell Lung ◽

Cell Lung Carcinoma ◽

In Vivo Experiments

Abstract Background: Lung cancer is a leading cause of cancer death around the world, while the Transthyretin (TTR) is a specific biomarkers for clinical diagnosis. However, its role in lung cancer remains to be unknown. Methods: In the present study, we made attempt to investigate effect of abnormal expression of TTR on Non-small-cell lung carcinoma (NSCLC) by overexpression or knockdown of TTR.To further investigate the mechanisms underlying the potential role of TTR in NSCLC, we searched and verified several signal pathways . In vivo experiments, to verify the effect of TTR overexpression on tumors.Results: We finded that up-regulated TTR obviously suppressed cell proliferation, migration, invasion and increased apoptosis.Significant suppression of phosphor-MAPK/ERK was observed in TTR-treated NSCLC cells, implying that TTR was important for cellular progress by regulating MAPK/ERK signaling pathway. In vivo experiment, overexpression of TTR promoted cell apoptosis and inhibited tumor growth. Conclusions: Overall, our results suggest that TTR has a potential anti-tumor effect in human NSCLC progression, which provides theoretical basis for the diagnosis and treatment of NSCLC.Above all, further understanding of TTR was useful for clinical care.

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Prognostic Role of TLE Family in Lung Adenocarcinoma

10.21203/rs.3.rs-80137/v1 ◽

2020 ◽

Author(s):

Qianli Ma ◽

Fei Xiao ◽

Huajie Xing ◽

Zhiyi Song ◽

Jin Zhang ◽

...

Keyword(s):

Lung Cancer ◽

Lung Adenocarcinoma ◽

Common Type ◽

Cancer Death ◽

Prognostic Role ◽

Independent Risk Factors ◽

Tcga Dataset ◽

The Relationship ◽

Enhancer Of Split

Abstract Background Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer death worldwide. Lung adenocarcinoma (LUAD) is the most common type of lung cancer. Transducin-like Enhancer of split (TLE) family proteins repress transcription by multiple mechanisms. The prognostic role of TLEs in LUAD is still unclear. Methods We took TCGA dataset to analyze the relationship between the expression of TLEs and LUAD outcome. Results The expression of TLEs were different between 59 normal and 513 tumor samples. High TLE1 and low TLE2 were associated with poor PFS and OS (all p＜0.050). Multivariate analysis demonstrated that high TLE1 and low TLE2 were independent risk factors. Moreover, the combination of TLE1 and TLE2 was a better tool in prognostication. Conclusions High TLE1 and low TLE2 expressions are independent adverse prognostic factors and can be used as prognostic biomarkers in LUAD.

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