scholarly journals PRMT5 Inhibition Promotes PD-L1 Expression and Immuno-Resistance in Lung Cancer

2022 ◽  
Vol 12 ◽  
Author(s):  
Rui Hu ◽  
Bingqian Zhou ◽  
Zheyi Chen ◽  
Shiyu Chen ◽  
Ningdai Chen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Cancer ◽  
Tumor Cell ◽  
Lung Tumor ◽  
Inhibitory Effect ◽  
Immunocompetent Mice ◽  
Immunocompromised Mice ◽  
Cell Expression

Protein arginine transferase 5 (PRMT5) has been implicated as an important modulator of tumorigenesis as it promotes tumor cell proliferation, invasion, and metastasis. Studies have largely focused on PRMT5 regulating intrinsic changes in tumors; however, the effects of PRMT5 on the tumor microenvironment and particularly immune cells are largely unknown. Here we found that targeting PRMT5 by genetic or pharmacological inhibition reduced lung tumor progression in immunocompromised mice; however, the effects were weakened in immunocompetent mice. PRMT5 inhibition not only decreased tumor cell survival but also increased the tumor cell expression of CD274 in vitro and in vivo, which activated the PD1/PD-L1 axis and eliminated CD8+T cell antitumor immunity. Mechanistically, PRMT5 regulated CD274 gene expression through symmetric dimethylation of histone H4R3, increased deposition of H3R4me2s on CD274 promoter loci, and inhibition of CD274 gene expression. Targeting PRMT5 reduced this inhibitory effect and promoted CD274 expression in lung cancer. However, PRMT5 inhibitors represent a double-edged sword as they may selectively kill cancer cells but may also disrupt the antitumor immune response. The combination of PRMT5 inhibition and ani-PD-L1 therapy resulted in an increase in the number and enhanced the function of tumor-infiltrating T cells. Our findings address an unmet clinical need in which combining PRMT5 inhibition with anti-PD-L1 therapy could be a promising strategy for lung cancer treatment.

scholarly journals Impact of the acidic environment on gene expression and functional parameters of tumors in vitro and in vivo

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Mandy Rauschner ◽  
Luisa Lange ◽  
Thea Hüsing ◽  
Sarah Reime ◽  
Alexander Nolze ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Death ◽  
Western Blot ◽  
Tumor Cell ◽  
Low Ph ◽  
Strong Increase ◽  
Acidic Ph ◽  
The Impact

Abstract Background The low extracellular pH (pHe) of tumors resulting from glycolytic metabolism is a stress factor for the cells independent from concomitant hypoxia. The aim of the study was to analyze the impact of acidic pHe on gene expression on mRNA and protein level in two experimental tumor lines in vitro and in vivo and were compared to hypoxic conditions as well as combined acidosis+hypoxia. Methods Gene expression was analyzed in AT1 prostate and Walker-256 mammary carcinoma of the rat by Next Generation Sequencing (NGS), qPCR and Western blot. In addition, the impact of acidosis on tumor cell migration, adhesion, proliferation, cell death and mitochondrial activity was analyzed. Results NGS analyses revealed that 147 genes were uniformly regulated in both cell lines (in vitro) and 79 genes in both experimental tumors after 24 h at low pH. A subset of 25 genes was re-evaluated by qPCR and Western blot. Low pH consistently upregulated Aox1, Gls2, Gstp1, Ikbke, Per3, Pink1, Tlr5, Txnip, Ypel3 or downregulated Acat2, Brip1, Clspn, Dnajc25, Ercc6l, Mmd, Rif1, Zmpste24 whereas hypoxia alone led to a downregulation of most of the genes. Direct incubation at low pH reduced tumor cell adhesion whereas acidic pre-incubation increased the adhesive potential. In both tumor lines acidosis induced a G1-arrest (in vivo) of the cell cycle and a strong increase in necrotic cell death (but not in apoptosis). The mitochondrial O2 consumption increased gradually with decreasing pH. Conclusions These data show that acidic pHe in tumors plays an important role for gene expression independently from hypoxia. In parallel, acidosis modulates functional properties of tumors relevant for their malignant potential and which might be the result of pH-dependent gene expression.

Synergy of nanodiamond-doxorubicin conjugates and PD-L1 blockade effectively turns tumor associated macrophages against tumor cells

2021 ◽  
Author(s):  
Huazhen Xu ◽  
Tongfei Li ◽  
Chao Wang ◽  
Yan Ma ◽  
Yan Liu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Cell ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Lung Cancer Cells ◽  
Dependent Manner ◽  
Tumor Associated Macrophages ◽  
M1 Type

Abstract Background: Tumor-associated macrophages (TAM) are the most abundant stromal cells in the tumor microenvironment. Turning the TAM against their host tumor cells is an intriguing therapeutic strategy particularly attractive for patients with immunologically “cold” tumors. This concept was mechanistically demonstrated on in vitro human and murine lung cancer cells and their corresponding TAM models through combinatorial use of nanodiamond-doxorubicin conjugates (Nano-DOX) and a PD-L1 blocking agent BMS-1. Nano-DOX are an agent previously proved to be able to stimulate tumor cells’ immunogenicity and thereby reactivate the TAM into the anti-tumor M1 phenotype. Results: Nano-DOX were first shown to stimulate the tumor cells and the TAM to release the cytokine HMGB1 which, regardless of its source, acted through the RAGE/NF-κB pathway to induce PD-L1 in the tumor cells and PD-L1/PD-1 in the TAM. Interestingly, Nano-DOX also induced NF-κB-dependent RAGE expression in the tumor cells and thus reinforced HMGB1’s action thereon. Then, BMS-1 was shown to enhance Nano-DOX-stimulated M1-type activation of TAM both by blocking Nano-DOX-induced PD-L1 in the TAM and by blocking tumor cell PD-L1 ligation with TAM PD-1. The TAM with enhanced M1-type repolarization both killed the tumor cells and suppressed their growth. BMS-1 could also potentiate Nano-DOX’s action to suppress tumor cell growth via blocking of Nano-DOX-induced PD-L1 therein. Finally, Nano-DOX and BMS-1 achieved synergistic therapeutic efficacy against in vivo tumor grafts in a TAM-dependent manner. Conclusions: PD-L1/PD-1 upregulation mediated by autocrine and paracrine activation of the HMGB1/RAGE/NF-κB signaling is a key response of lung cancer cells and their TAM to stress, which can be induced by Nano-DOX. Blockade of Nano-DOX-induced PD-L1, both in the cancer cells and the TAM, achieves enhanced activation of TAM-mediated anti-tumor response.

scholarly journals Tumorigenicity of simian virus 40-hepatocyte cell lines: effect of in vitro and in vivo passage on expression of liver-specific genes and oncogenes.

1988 ◽  
Vol 8 (10) ◽  
pp. 4492-4501 ◽  
Author(s):  
C D Woodworth ◽  
J W Kreider ◽  
L Mengel ◽  
T Miller ◽  
Y L Meng ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tumor Cell ◽  
Cell Lines ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Simian Virus 40 ◽  
Simian Virus ◽  
Tumor Cell Lines ◽  
Glutathione S Transferase

Five simian virus 40 (SV40)-hepatocyte cell lines were examined for tumorigenicity and the effect of in vitro passage on the expression of four liver-specific genes (albumin, transferrin, alpha 1-antitrypsin, and phosphoenolpyruvate carboxykinase), two oncogenes (c-Ha-ras and c-raf), and two genes associated with hepatocarcinogenesis (alpha-fetoprotein and placental-type glutathione-S-transferase). At low passage (12 to 22), all five cell lines expressed the four liver-specific genes at levels similar to those in the liver and were not tumorigenic or were weakly tumorigenic. At high passage (33 to 61), the cell lines formed carcinomas, and four out of five cell lines produced primary tumors that metastasized. At least two cell lines produced well-differentiated hepatocellular carcinomas that expressed liver-specific RNAs. Levels of expression of liver-specific genes changed with time in culture. Some of the changes in liver-specific gene expression in the tumor tissue (such as for the phosphoenolpyruvate carboxykinase gene) paralleled those that occurred with in vitro passage, while other changes (such as for the albumin gene) did not parallel those that occurred with in vitro passage. Correlations between enhanced expression of c-Ha-ras and tumorigenic potential and between the process of SV40 immortalization and induced expression of c-raf and glutathione-S-transferase-P were observed. Induction of alpha-fetoprotein was detected with in vitro and in vivo passage only in the CWSV14 cell line and was paralleled by diminished albumin expression. In conclusion, we developed a model system with five SV40-hepatocyte cell lines, tumors induced by them, and tumor cell lines to examine changes in gene expression that accompany the progression from a normal cell to a hepatocellular carcinoma. Because the SV40-hepatocyte cell lines and tumor cell lines remain highly differentiated and vary in the magnitude of expression of specific genes, they can be used to study the molecular mechanisms regulating gene expression, in particular those regulating specific genes associated with differentiation.

scholarly journals MINDIN secretion by prostate tumors induces premetastatic changes in bone via β-catenin

2020 ◽  
Vol 27 (7) ◽  
pp. 441-456
Author(s):  
Juan A Ardura ◽  
Luis Álvarez-Carrión ◽  
Irene Gutiérrez-Rojas ◽  
Peter A Friedman ◽  
Arancha R Gortázar ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Tumor Cell ◽  
Ex Vivo ◽  
Prostate Tumor ◽  
Tumor Cell Adhesion ◽  
Prostate Tumors ◽  
Cell Homing

Bone metastases are common in advanced prostate cancer patients, but mechanisms by which specific pro-metastatic skeletal niches are formed before tumor cell homing are unclear. We aimed to analyze the effects of proteins secreted by primary prostate tumors on the bone microenvironment before the settlement and propagation of metastases. Here, using an in vivo pre-metastatic prostate cancer model based on the implantation of prostate adenocarcinoma TRAMP-C1 cells in immunocompetent C57BL/6 mice, we identify MINDIN as a prostate tumor secreted protein that induces bone microstructural and bone remodeling gene expression changes before tumor cell homing. Associated with these changes, increased tumor cell adhesion to the endosteum ex vivo and to osteoblasts in vitro was observed. Furthermore, MINDIN promoted osteoblast proliferation and mineralization and monocyte expression of osteoclast markers. β-catenin signaling pathway revealed to mediate MINDIN actions on osteoblast gene expression but failed to affect MINDIN-induced adhesion to prostate tumor cells or monocyte differentiation to osteoclasts. Our study evidences that MINDIN secretion by primary prostate tumors creates a favorable bone environment for tumor cell homing before metastatic spread.

scholarly journals NLRR1 Is a Potential Therapeutic Target in Neuroblastoma and MYCN-Driven Malignant Cancers

2021 ◽  
Vol 11 ◽  
Author(s):  
Atsushi Takatori ◽  
Shamim Hossain ◽  
Atsushi Ogura ◽  
Jesmin Akter ◽  
Yohko Nakamura ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Cell ◽  
Inhibitory Effect ◽  
Tumor Cell Proliferation ◽  
Growth Inhibitory Effect ◽  
Extracellular Domains ◽  
Growth Inhibitory ◽  
Fniii Domain

Receptor tyrosine kinases (RTKs) receive different modulation before transmitting proliferative signals. We previously identified neuronal leucine-rich repeat 1 (NLRR1) as a positive regulator of EGF and IGF-1 signals in high-risk neuroblastoma cells. Here, we show that NLRR1 is up-regulated in various adult cancers and acts as a key regulator of tumor cell proliferation. In the extracellular domains of NLRR1, fibronectin type III (FNIII) domain is responsible for its function to promote cell proliferation. We generated monoclonal antibodies against the extracellular domains of NLRR1 (N1mAb) and screened the positive N1mAbs for growth inhibitory effect. The treatment of N1mAbs reduces tumor cell proliferation in vitro and in vivo, and sensitizes the cells to EGFR inhibitor, suggesting that NLRR1 is a novel regulatory molecule of RTK function. Importantly, epitope mapping analysis has revealed that N1mAbs with growth inhibitory effect recognize immunoglobulin-like and FNIII domains of NLRR1, which also indicates the importance of FNIII domain in the function of NLRR1. Thus, the present study provides a new insight into the development of a cancer therapy by targeting NLRR1 as a modulator of proliferative signals on cellular membrane of tumor cells.

Abstract 1291: Tumor growth inhibitory effect in EIF4B silenced in vitro and in vivo lung cancer models

2012 ◽  
Author(s):  
Jung-Young Shin ◽  
Xiang-Hua Zhang ◽  
Jeong-Oh Kim ◽  
Ji-Eun Oh ◽  
Hiun Suk Chae ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Growth ◽  
Inhibitory Effect ◽  
Growth Inhibitory Effect ◽  
Growth Inhibitory ◽  
Cancer Models

scholarly journals Interferon Regulatory Factor 9 Promotes Lung Cancer Progression via Regulation of Versican

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 208
Author(s):  
David Brunn ◽  
Kati Turkowski ◽  
Stefan Günther ◽  
Andreas Weigert ◽  
Thomas Muley ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Progression ◽  
Lung Tumor ◽  
Interferon Regulatory Factor ◽  
Human Lung Cancer ◽  
Regulatory Factor ◽  
And Migration ◽  
Proliferation And Migration

Transcription factors can serve as links between tumor microenvironment signaling and oncogenesis. Interferon regulatory factor 9 (IRF9) is recruited and expressed upon interferon stimulation and is dependent on cofactors that exert in tumor-suppressing or oncogenic functions via the JAK-STAT pathway. IRF9 is frequently overexpressed in human lung cancer and is associated with decreased patient survival; however, the underlying mechanisms remain to be elucidated. Here, we used stably transduced lung adenocarcinoma cell lines (A549 and A427) to overexpress or knockdown IRF9. Overexpression led to increased oncogenic behavior in vitro, including enhanced proliferation and migration, whereas knockdown reduced these effects. These findings were confirmed in vivo using lung tumor xenografts in nude mice, and effects on both tumor growth and tumor mass were observed. Using RNA sequencing, we identified versican (VCAN) as a novel downstream target of IRF9. Indeed, IRF9 and VCAN expression levels were found to be correlated. We showed for the first time that IRF9 binds at a newly identified response element in the promoter region of VCAN to regulate its transcription. Using an siRNA approach, VCAN was found to enable the oncogenic properties (proliferation and migration) of IRF9 transduced cells, perhaps with CDKN1A involvement. The targeted inhibition of IRF9 in lung cancer could therefore be used as a new treatment option without multimodal interference in microenvironment JAK-STAT signaling.

Inhibitory effect of riccardin D on growth of human non-small cell lung cancer: In vitro and in vivo studies

Lung Cancer ◽  
2012 ◽  
Vol 76 (3) ◽  
pp. 300-308 ◽  
Author(s):  
Xia Xue ◽  
De-Fu Sun ◽  
Cui-Cui Sun ◽  
Hui-Ping Liu ◽  
Bin Yue ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Inhibitory Effect ◽  
Small Cell ◽  
In Vivo Studies ◽  
Small Cell Lung

scholarly journals Borrelia burgdorferi Gene Expression In Vivo and Spirochete Pathogenicity

2000 ◽  
Vol 68 (3) ◽  
pp. 1222-1230 ◽  
Author(s):  
Juan Anguita ◽  
Swapna Samanta ◽  
Beatriz Revilla ◽  
Kyoungho Suk ◽  
Subrata Das ◽  
...  
Keyword(s):  
Gene Expression ◽  
Borrelia Burgdorferi ◽  
Subsequent Development ◽  
Scid Mice ◽  
Expression Library ◽  
Genomic Expression ◽  
C3h Mice ◽  
Immunocompetent Mice

ABSTRACT Borrelia burgdorferi spirochetes that do not cause arthritis or carditis were developed and used to investigate Lyme disease pathogenesis. A clonal isolate of B. burgdorferiN40 (cN40), which induces disease in C3H/HeN (C3H) mice, was repeatedly passaged in vitro to generate nonpathogenic spirochetes. The passage 75 isolate (N40-75) was infectious for C3H mice but did not cause arthritis or carditis, and spirochetes were at low levels or absent in the joints or hearts, respectively. N40-75 could, however, cause disease in severe combined immunodeficient (SCID) mice, suggesting that the response in immunocompetent mice prevented effective spirochete dissemination and the subsequent development of arthritis and carditis. Administration of immune sera at 4 days after spirochete challenge aborted N40-75, but not cN40, infection in SCID mice. A B. burgdorferi genomic expression library was differentially probed with sera from cN40- and N40-75-infected mice, to identify genes that may not be effectively expressed by N40-75 in vivo. N40-75 was defective in the up-regulation of several genes that are preferentially expressed during mammalian infection, including dbpAB,bba64, and genes that map to the cp32 family of plasmids. These data suggest that adaptation and gene expression may be required for B. burgdorferi to effectively colonize the host, evade humoral responses, and cause disease.

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