ResearchPad - cancer-biology https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[The tumor microenvironment as a metabolic barrier to effector T cells and immunotherapy]]> https://www.researchpad.co/article/N0a351c1f-39d5-481a-9e94-df671572819a Breakthroughs in anti-tumor immunity have led to unprecedented advances in immunotherapy, yet it is now clear that the tumor microenvironment (TME) restrains immunity. T cells must substantially increase nutrient uptake to mount a proper immune response and failure to obtain sufficient nutrients or engage the appropriate metabolic pathways can alter or prevent effector T cell differentiation and function. The TME, however, can be metabolically hostile due to insufficient vascular exchange and cancer cell metabolism that leads to hypoxia, depletion of nutrients, and accumulation of waste products. Further, inhibitory receptors present in the TME can inhibit T cell metabolism and alter T cell signaling both directly and through release of extracellular vesicles such as exosomes. This review will discuss the metabolic changes that drive T cells into different stages of their development and how the TME imposes barriers to the metabolism and activity of tumor infiltrating lymphocytes.

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<![CDATA[Squamous trans-differentiation of pancreatic cancer cells promotes stromal inflammation]]> https://www.researchpad.co/article/N58b21af8-f705-4f07-9c06-f212debcae5f A highly aggressive subset of pancreatic ductal adenocarcinomas undergo trans-differentiation into the squamous lineage during disease progression. Here, we investigated whether squamous trans-differentiation of human and mouse pancreatic cancer cells can influence the phenotype of non-neoplastic cells in the tumor microenvironment. Conditioned media experiments revealed that squamous pancreatic cancer cells secrete factors that recruit neutrophils and convert pancreatic stellate cells into cancer-associated fibroblasts (CAFs) that express inflammatory cytokines at high levels. We use gain- and loss-of-function approaches to show that squamous-subtype pancreatic tumor models become enriched with neutrophils and inflammatory CAFs in a p63-dependent manner. These effects occur, at least in part, through p63-mediated activation of enhancers at pro-inflammatory cytokine loci, which includes IL1A and CXCL1 as key targets. Taken together, our findings reveal enhanced tissue inflammation as a consequence of squamous trans-differentiation in pancreatic cancer, thus highlighting an instructive role of tumor cell lineage in reprogramming the stromal microenvironment.

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<![CDATA[Interferon-beta treatment increases human papillomavirus early gene transcription and viral plasmid genome replication by activating interferon regulatory factor (IRF)-1]]> https://www.researchpad.co/article/Neaa4dede-e836-4ee7-84f0-6f50ffb79137

Abstract

Interferons (IFNs) have been used to treat mucosal lesions caused by human papillomavirus (HPV) infection, such as intraepithelial precursor lesions to cancer of the uterine cervix, genital warts or recurrent respiratory papillomatosis, to potentially reduce or eliminate replicating HPV plasmid genomes. Mucosal HPVs have evolved mechanisms that impede IFN-β synthesis and downregulate genes induced by IFN. Here we show that these HPV types directly subvert a cellular transcriptional response to IFN-β as a potential boost in infection. Treatment with low levels of human IFN-β induced initial amplification of HPV-16 and HPV-11 plasmid genomes and increased HPV-16 or HPV-31 DNA copy numbers up to 6-fold in HPV-immortalized keratinocytes. IFN treatment also increased early gene transcription from the major early gene promoters in HPV-16, HPV-31 and HPV-11. Furthermore, mutagenesis of the viral genomes and ectopic interferon regulatory factor (IRF) expression in transfection experiments using IRF-1 −/− , IRF-2 −/− and dual knockout cell lines determined that these responses are due to the activation of IRF-1 interaction with a conserved interferon response element demonstrated in several mucosal HPV early gene promoters. Our results provide a molecular explanation for the varying clinical outcomes of IFN therapy of papillomatoses and define an assay for the modulation of the HPV gene program by IFNs as well as other cytokines and signaling molecules in infection and therapy.

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<![CDATA[Drosophila TRIM32 cooperates with glycolytic enzymes to promote cell growth]]> https://www.researchpad.co/article/Nb3ac9dbe-224e-40a1-9642-93ccee365eab

Cell growth and/or proliferation may require the reprogramming of metabolic pathways, whereby a switch from oxidative to glycolytic metabolism diverts glycolytic intermediates towards anabolic pathways. Herein, we identify a novel role for TRIM32 in the maintenance of glycolytic flux mediated by biochemical interactions with the glycolytic enzymes Aldolase and Phosphoglycerate mutase. Loss of Drosophila TRIM32, encoded by thin (tn), shows reduced levels of glycolytic intermediates and amino acids. This altered metabolic profile correlates with a reduction in the size of glycolytic larval muscle and brain tissue. Consistent with a role for metabolic intermediates in glycolysis-driven biomass production, dietary amino acid supplementation in tn mutants improves muscle mass. Remarkably, TRIM32 is also required for ectopic growth - loss of TRIM32 in a wing disc-associated tumor model reduces glycolytic metabolism and restricts growth. Overall, our results reveal a novel role for TRIM32 for controlling glycolysis in the context of both normal development and tumor growth.

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<![CDATA[GPC1 specific CAR-T cells eradicate established solid tumor without adverse effects and synergize with anti-PD-1 Ab]]> https://www.researchpad.co/article/N5adc05b9-82c7-4a45-a8c2-a8fd630f550b

Current xenogeneic mouse models cannot evaluate on-target off-tumor adverse effect, hindering the development of chimeric antigen receptor (CAR) T cell therapies for solid tumors, due to limited human/mouse cross-reactivity of antibodies used in CAR and sever graft-versus-host disease induced by administered human T cells. We have evaluated safety and antitumor efficacy of CAR-T cells targeting glypican-1 (GPC1) overexpressed in various solid tumors. GPC1-specific human and murine CAR-T cells generated from our original anti-human/mouse GPC1 antibody showed strong antitumor effects in xenogeneic and syngeneic mouse models, respectively. Importantly, the murine CAR-T cells enhanced endogenous T cell responses against a non-GPC1 tumor antigen through the mechanism of antigen-spreading and showed synergistic antitumor effects with anti-PD-1 antibody without any adverse effects in syngeneic models. Our study shows the potential of GPC1 as a CAR-T cell target for solid tumors and the importance of syngeneic and xenogeneic models for evaluating their safety and efficacy.

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<![CDATA[LINC00311 promotes cancer stem‐like properties by targeting miR‐330‐5p/TLR4 pathway in human papillary thyroid cancer]]> https://www.researchpad.co/article/N725b29de-8568-466c-9cb8-1c5a26320462

Abstract

Growing evidence has suggested that long noncoding RNAs (lncRNAs) play an essential role in the progression of papillary thyroid cancer (PTC). LncRNA LINC00311 was found to be able to regulate many cellular process in several diseases. However, the function and regulatory mechanism of LINC00311 remains unclear in PTC. In the present study, the results showed that the expression of LINC00311 was upregulated in PTC tissues and cells. Furthermore, knockdown of LINC00311 dramatically suppressed spheroid formation, proliferation, migration, and invasion in PTC cells in vitro. Mechanistic investigations revealed that LINC00311 was negatively correlated with the expression of miR‐330‐5p, meanwhile, TLR4 was a direct target of miR‐330‐5p. In addition, rescue assays further determined that LINC00311 contributed to the progression of PTC through regulating TLR4 expression. Taken together, these findings indicated that LINC00311 could promote cancer stem‐like properties by targeting miR‐330‐5p/TLR4 pathway in PTC.

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<![CDATA[RAPTOR promotes colorectal cancer proliferation by inducing mTORC1 and upregulating ribosome assembly factor URB1]]> https://www.researchpad.co/article/N3c231eca-02a8-4478-8bd1-f5bd9c0984dd

Abstract

Mammalian target of rapamycin complex 1 (mTORC1) is evolutionally conserved and frequently activated in various tumors, including colorectal cancer (CRC). It has been reported that the ribosome assembly factor Urb1 acts downstream of mTORC1/raptor signaling and contributes to digestive organ development in zebrafish. Previously, we highlighted that URB1 was overexpressed in CRC. Here, we assessed the mTORC1/regulatory associated protein with mTOR (RAPTOR)‐URB1 axis in CRC tumorigenesis. We found that RAPTOR was overexpressed in CRC tissues and cell lines, was a favorable predictor in patients with CRC, and positively correlated with URB1. Silencing of RAPTOR suppressed CRC cell proliferation and migration and induced cell cycle arrest and apoptosis in vitro and inhibited xenograft growth in vivo. Moreover, ectopic overexpression of RAPTOR exerted an inverse biological phenotype. Knockdown of RAPTOR quenched mTORC1 activity and reduced the expression of URB1 and cyclinA2 (CCNA2). In contrast, overexpression of RAPTOR activated mTORC1 and upregulated URB1 and CCNA2. Furthermore, URB1 and CCNA2 expression were also impeded by rapamycin, which is a specific inhibitor of mTORC1. Thus, RAPTOR promoted CRC proliferation, migration, and cell cycle progression by inducing mTORC1 signaling and transcriptional activation of both URB1 and CCNA2. Taken together, we concluded that RAPTOR has the potential to serve as a novel biomarker and therapeutic target for CRC.

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<![CDATA[ TOB1 suppresses proliferation in K‐Ras wild‐type pancreatic cancer]]> https://www.researchpad.co/article/N7b19d4bc-9ce1-48a6-9126-fbed4030411b

Abstract

TOB1 participates in various kinds of cancers. However, its role in pancreatic cancer has rarely been reported. In this study, we explored the expression and mechanisms of TOB1 in regulating the malignant phenotype of pancreatic cancer cells. TOB1 expression was determined by data mining and immunohistochemistry (IHC), and its localization was observed by immunofluorescence. CCK‐8 cell proliferation, colony formation, flow cytometric, transwell migration, and Western blot (WB) assays were used to examine how it impacts the malignant phenotype of pancreatic cancer. Furthermore, Foxa2 binding to TOB1 was tested by dual‐luciferase reporter assays, and RNA‐Seq was performed to identify signaling pathways. We found TOB1 was downregulated in pancreatic cancer tissues and was mainly located in the cytoplasm. TOB1 overexpression reduced the proliferation of K‐Ras wild‐type pancreatic cancer cells but made no difference to cell migration and invasion. Foxa2 overexpression significantly enhanced TOB1 promoter activity. Moreover, overexpressing TOB1 substantially enriched the calcium pathway in K‐Ras wild‐type pancreatic cancer cells. In conclusion, TOB1 may suppress the proliferation of K‐Ras wild‐type pancreatic cancer cells by regulating calcium pathway genes.

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<![CDATA[MicroRNA‐221 promotes breast cancer resistance to adriamycin via modulation of PTEN/Akt/mTOR signaling]]> https://www.researchpad.co/article/Na52de234-77ba-4afb-9c25-0afe9f5417f5

Abstract

As a prevalent tumor among women, breast cancer is still an incurable disease due to drug resistance. In this study, we report microRNA‐221 to have a significant effect on breast cancer resistance to adriamycin. The microRNA‐221 is elevated in tumor tissue compared with nearby nontumor samples, as well as in breast cancer cell line with adriamycin resistance (MCF‐7/ADR) compared to its parental line (MCF‐7) and the normal breast epithelial cell line (MCF‐10A). Enforced level of microRNA‐221 promotes cancer resistance to adriamycin, which in turn sustains cell survival and exacerbates malignant formation. Reciprocally, the silence of microRNA‐221 in cancer cells augments the sensitivity to chemotherapy, thereby resulting in enhanced apoptosis of MCF‐7/ADR cells. Mechanistically, we identify PTEN as a direct target of microRNA‐221, which was conversely associated with a microRNA‐221 level in breast tumors. The knock‐down of PTEN partially reversed the stimulatory role of microRNA‐221 in the modulation of the Akt/mTOR signaling. Taken together, these findings suggest microRNA‐221 suppresses PTEN transcription and activates Akt/mTOR pathway, which in turn enhances breast cancer resistance to adriamycin and promotes cancer development. Our data thus illuminate the microRNA‐221/PTEN axis may act as a promising strategy for the treatment of chemotherapy‐resistant breast tumors.

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<![CDATA[A phase 2 study of GVAX colon vaccine with cyclophosphamide and pembrolizumab in patients with mismatch repair proficient advanced colorectal cancer]]> https://www.researchpad.co/article/N21160926-fe4e-4f58-a889-9204968e1b56

Abstract

Background

Mismatch repair proficient (MMRp) colorectal cancer (CRC) has been refractory to single‐agent programmed cell death protein 1 (PD1) inhibitor therapy. Colon GVAX is an allogeneic, whole‐cell, granulocyte‐macrophage colony‐stimulating factor ‐secreting cellular immunotherapy that induces T‐cell immunity against tumor‐associated antigens and has previously been studied in combination with low‐dose cyclophosphamide (Cy) to inhibit regulatory T cells.

Methods

We conducted a single‐arm study of GVAX/Cy in combination with the PD1 inhibitor pembrolizumab in patients with advanced MMRp CRC. Patients received pembrolizumab plus Cy on day 1, GVAX on day 2, of a 21‐day cycle. The primary endpoint was the objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary objectives included safety, overall survival, progression‐free survival, changes in carcinoembryonic antigen (CEA) levels, and immune‐related correlates.

Results

Seventeen patients were enrolled. There were no objective responses, and the disease control rate was 18% by RECIST 1.1. The median progression‐free survival was 82 days (95% confidence interval [CI], 48‐97 days) and the median overall survival was 213 days (95% CI 179‐441 days). Biochemical responses (≥30% decline in CEA) were observed in 7/17 (41%) of patients. Grade ≥ 3 treatment‐related adverse events were observed in two patients (hemolytic anemia and corneal transplant rejection). Paired pre‐ and on‐treatment biopsy specimens showed increases in programmed death‐ligand 1 expression and tumor necrosis in a subset of patients.

Conclusions

GVAX/Cy plus pembrolizumab failed to meet its primary objective in MMRp CRC. Biochemical responses were observed in a subset of patients and have not previously been observed with pembrolizumab monotherapy in MMRp CRC, indicating that GVAX may modulate the antitumor immune response.

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<![CDATA[Combined treatment with N‐acetylcysteine and gefitinib overcomes drug resistance to gefitinib in NSCLC cell line]]> https://www.researchpad.co/article/Nae154cae-bdbf-40c0-baf1-c484b473c77b

Abstract

We aimed to explore the molecular substrate underlying EGFR‐TKI resistance and investigate the effects of N‐acetylcysteine (NAC) on reversing EGFR‐TKI resistance. In the current research, the effects of NAC in combination with gefitinib on reversing gefitinib resistance were examined using CCK‐8 assay, combination index (CI) method, matrigel invasion assay, wound‐healing assay, flow cytometry, western blot, and quantitative real‐time PCR (qRT‐PCR). CCK8 assay showed that NAC plus gefitinib combination overcame EGFR‐TKI resistance in non‐small cell lung cancer (NSCLC) cells by lowering the value of half maximal inhibitory concentration (IC50). CI calculations demonstrated a synergistic effect between the two drugs (CI < 1). Matrigel invasion assay and wound healing assay demonstrated a decrease in migration and invasion ability of PC‐9/GR cells after NAC and gefitinib treatment. Flow cytometry displayed enhanced apoptosis in the combination group. Western blot and qRT‐PCR revealed that increased E‐cadherin and decreased vimentin in the combination group. When PP2 was administered with gefitinib, the same effects were seen. Our findings suggest that NAC could restore the sensitivity of gefitinib‐resistant NSCLC cells to gefitinib via suppressing Src activation and reversing epithelial‐mesenchymal transition.

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<![CDATA[Epistatic effect of TLR3 and cGAS‐STING‐IKKε‐TBK1‐IFN signaling variants on colorectal cancer risk]]> https://www.researchpad.co/article/N5b61a5c3-b694-423d-a52e-fd79d358dd6a

Abstract

Objective

The TLR3/cGAS‐STING‐IFN signaling has recently been reported to be disturbed in colorectal cancer due to deregulated expression of the genes involved. Our study aimed to investigate the influence of potential regulatory variants in these genes on the risk of sporadic colorectal cancer (CRC) in a Czech cohort of 1424 CRC patients and 1114 healthy controls.

Methods

The variants in the TLR3, CGAS, TMEM173, IKBKE, and TBK1 genes were selected using various online bioinformatic tools, such as UCSC browser, HaploReg, Regulome DB, Gtex Portal, SIFT, PolyPhen2, and miRNA prediction tools.

Results

Logistic regression analysis adjusted for age and sex detected a nominal association between CRC risk and three variants, CGAS rs72960018 (OR: 1.68, 95% CI: 1.11‐2.53, P‐value = .01), CGAS rs9352000 (OR: 2.02, 95% CI: 1.07‐3.84, P‐value = .03) and TMEM173 rs13153461 (OR: 1.53, 95% CI: 1.03‐2.27, P‐value = .03). Their cumulative effect revealed a threefold increased CRC risk in carriers of 5‐6 risk alleles compared to those with 0‐2 risk alleles. Epistatic interactions between these genes and the previously genotyped IFNAR1, IFNAR2, IFNA, IFNB, IFNK, IFNW, IRF3, and IRF7 genes, were computed to test their effect on CRC risk. Overall, we obtained nine pair‐wise interactions within and between the CGAS, TMEM173, IKBKE, and TBK1 genes. Two of them remained statistically significant after Bonferroni correction. Additional 52 interactions were observed when IFN variants were added to the analysis.

Conclusions

Our data suggest that epistatic interactions and a high number of risk alleles may play an important role in CRC carcinogenesis, offering novel biological understanding for the CRC management.

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<![CDATA[Membrane interactions of the globular domain and the hypervariable region of KRAS4b define its unique diffusion behavior]]> https://www.researchpad.co/article/Nd8849615-3b15-4df6-81b4-e5f774561a49

The RAS proteins are GTP-dependent switches that regulate signaling pathways and are frequently mutated in cancer. RAS proteins concentrate in the plasma membrane via lipid-tethers and hypervariable region side-chain interactions in distinct nano-domains. However, little is known about RAS membrane dynamics and the details of RAS activation of downstream signaling. Here, we characterize RAS in live human and mouse cells using single-molecule-tracking methods and estimate RAS mobility parameters. KRAS4b exhibits confined mobility with three diffusive states distinct from the other RAS isoforms (KRAS4a, NRAS, and HRAS); and although most of the amino acid differences between RAS isoforms lie within the hypervariable region, the additional confinement of KRAS4b is largely determined by the protein’s globular domain. To understand the altered mobility of an oncogenic KRAS4b, we used complementary experimental and molecular dynamics simulation approaches to reveal a detailed mechanism.

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<![CDATA[Functional heterogeneity of lymphocytic patterns in primary melanoma dissected through single-cell multiplexing]]> https://www.researchpad.co/article/N396c958d-aa60-4411-800f-44cc52755fce

In melanoma, the lymphocytic infiltrate is a prognostic parameter classified morphologically into ‘brisk’, ‘non-brisk’ and ‘absent’ entailing a functional association that has never been proved. Recently, it has been shown that lymphocytic populations can be very heterogeneous, and that anti-PD-1 immunotherapy supports activated T cells. Here, we characterize the immune landscape in primary melanoma by high-dimensional single-cell multiplex analysis in tissue sections (MILAN technique) followed by image analysis, RT-PCR and shotgun proteomics. We observed that the brisk and non-brisk patterns are heterogeneous functional categories that can be further sub-classified into active, transitional or exhausted. The classification of primary melanomas based on the functional paradigm also shows correlation with spontaneous regression, and an improved prognostic value when compared to that of the brisk classification. Finally, the main inflammatory cell subpopulations that are present in the microenvironment associated with activation and exhaustion and their spatial relationships are described using neighbourhood analysis.

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<![CDATA[Merkel cell polyomavirus oncoproteins induce microRNAs that suppress multiple autophagy genes]]> https://www.researchpad.co/article/N10fc8659-b69a-49da-896e-589ff00be3f7

Viruses can inhibit host autophagy through multiple mechanisms, and evasion of autophagy plays an important role in immune suppression and viral oncogenesis. Merkel cell polyomavirus (MCPyV) T‐antigens are expressed and involved in the pathogenesis of a large proportion of Merkel cell carcinoma (MCC). Yet, how MCPyV induces tumorigenesis is not fully understood. Herein, we show that MCPyV T‐antigens induce miR‐375, miR‐30a‐3p and miR‐30a‐5p expressions, which target multiple key genes involved in autophagy, including ATG7, SQSTM1 (p62) and BECN1. In MCC tumors, low expression of ATG7 and p62 are associated with MCPyV‐positive tumors. Ectopic expression of MCPyV small T‐antigen and truncated large T‐antigen (LT), but not the wild‐type LT, resulted in autophagy suppression, suggesting the importance of autophagy evasion in MCPyV‐mediated tumorigenesis. Torin‐1 treatment induced cell death, which was attenuated by autophagy inhibitor, but not pan‐caspase inhibitor, suggesting a potential role of autophagy in promoting cell death in MCC. Conceptually, our study shows that MCPyV oncoproteins suppress autophagy to protect cancer cells from cell death, which contribute to a better understanding of MCPyV‐mediated tumorigenesis and potential MCC treatment.

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<![CDATA[Understanding the glioblastoma immune microenvironment as basis for the development of new immunotherapeutic strategies]]> https://www.researchpad.co/article/Nfb8a96f7-85ab-4795-ab30-daa0fc0a4747

Cancer immunotherapy by immune checkpoint blockade has proven its great potential by saving the lives of a proportion of late stage patients with immunogenic tumor types. However, even in these sensitive tumor types, the majority of patients do not sufficiently respond to the therapy. Furthermore, other tumor types, including glioblastoma, remain largely refractory. The glioblastoma immune microenvironment is recognized as highly immunosuppressive, posing a major hurdle for inducing immune-mediated destruction of cancer cells. Scattered information is available about the presence and activity of immunosuppressive or immunostimulatory cell types in glioblastoma tumors, including tumor-associated macrophages, tumor-infiltrating dendritic cells and regulatory T cells. These cell types are heterogeneous at the level of ontogeny, spatial distribution and functionality within the tumor immune compartment, providing insight in the complex cellular and molecular interplay that determines the immune refractory state in glioblastoma. This knowledge may also yield next generation molecular targets for therapeutic intervention.

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<![CDATA[Long noncoding RNA cytoskeleton regulator RNA promotes cell invasion and metastasis by titrating miR‐613 to regulate ANXA2 in nasopharyngeal carcinoma]]> https://www.researchpad.co/article/Ncf485a46-4eb6-4537-9f3a-f5a0304db7e4

Abstract

Background

Nasopharyngeal carcinoma (NPC) is one of the most frequent head and neck malignant tumors. Long noncoding RNAs play critical roles in tumorigenesis.

Methods

Real‐time quantitative PCR arrays were used to evaluate the expression levels of cytoskeleton regulator RNA (CYTOR) in NPC tissues and cells. Cell counting kit‐8 and colony formation analyses were used to test the NPC cell viability, while wound healing and transwell assays were employed to detect cell invasion and migration ability. Luciferase reporter assay and Western blot analyses were employed to explore the relationships among CYTOR, miR‐613, and ANXA2.

Results

We found that CYTOR expression was elevated both in NPC tissues and cells. Functional assays revealed that CYTOR promoted the invasion and migration of NPC cells. The established spontaneous lymph node metastasis model also confirmed that CYTOR promoted NPC cell metastasis in vivo. Mechanically, we found that the subcellular localization of CYTOR mostly occurred in the cell cytoplasm. Luciferase reporter and RIP assays confirmed that CYTOR functioned as the molecular sponge of miR‐613. Subsequent experiments confirmed that ANXA2 was directly targeted by miR‐613. Gain‐ and loss‐of‐function studies further confirmed that CYTOR induced the upregulation of ANXA2 by competitively binding to miR‐613, thus leading to NPC metastasis.

Conclusion

Our results highlight the importance of CYTOR in NPC development and provide new insights into potential therapeutic targets for NPC.

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<![CDATA[LncRNA GMDS‐AS1 inhibits lung adenocarcinoma development by regulating miR‐96‐5p/CYLD signaling]]> https://www.researchpad.co/article/Ne590859c-6a1a-4ea6-8806-509695ac86c4

Abstract

According to the global cancer statistic, lung cancer is one of the most dangerous tumors, which poses a serious threat to human health. Exploration the mechanism of lung cancer and new targeted therapeutic measures is always the hot topic. Long noncoding RNA (lncRNA) is an important factor affecting the development of tumors. However, the research on the mechanism of lncRNA in the progress of lung cancer needs to be further expanded. In this study, we found that the expression of lncRNA GMDS‐AS1 was significantly reduced in lung adenocarcinoma (LUAD) tissues and cells. Upregulated GMDS‐AS1 can significantly inhibit the proliferation of LUAD cells and promote cell apoptosis in vitro and in vivo. The results indicate that GMDS‐AS1 acts as a tumor suppressor gene to affect the development of LUAD. Further studies revealed that GMDS‐AS1 is a target gene of miR‐96‐5p, and GMDS‐AS1 regulates proliferation and apoptosis of LUAD cells in association with miR‐96‐5p. In addition, we also confirmed that CYLD lysine 63 deubiquitinase (CYLD) is also a target gene of miR‐96‐5p. Through various validations, we confirmed that GMDS‐AS1 can act as a ceRNA to upregulate the expression of CYLD by sponging miR‐96‐5p. Moreover, the intervention of GMDS‐AS1/miR‐96‐5p/CYLD network can regulate the proliferation and apoptosis of LUAD cells. In this study, we revealed that the GMDS‐AS1/miR‐96‐5p/CYLD network based on ceRNA mechanism plays an important role in the development of LUAD and provides a new direction and theoretical basis for targeted therapy of LUAD.

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<![CDATA[Combination of aloin and metformin enhances the antitumor effect by inhibiting the growth and invasion and inducing apoptosis and autophagy in hepatocellular carcinoma through PI3K/AKT/mTOR pathway]]> https://www.researchpad.co/article/N9ed9f8ac-edf8-4bcf-bafe-cc551cad99e9

Abstract

Hepatocellular carcinoma (HCC) is a devastating and highly metastatic cancer worldwide. Metformin (MET) is the priority drug for treatment of type 2 diabetes; however, it possesses multiple biological effects like anticancer and hepatoprotective activity. Herein, we examined the effects of aloin (barbaloin) and MET as well as combination treatment in HCC cell line in vitro and in vivo. As a result, aloin and MET alone exhibited inhibitory effects on proliferation and invasion of HepG2 and Bel‐7402 cells. Specially, combination treatment of aloin and MET showed enhanced inhibitory effects in vitro. Aloin and MET alone induced apoptosis and autophagy in vitro. Similarly, aloin and MET cooperated to promote apoptosis and autophagy in HepG2 and Bel‐7402 cells. In the HepG2 xenograft models, aloin in combination with MET confine tumor growth and facilitate apoptosis and autophagy. Both the in vitro and in vivo results showed that aloin and MET alone as well as combination treatment activated the PI3K/AKT/mTOR pathway. Overall, our research demonstrated that the concomitant treatment with aloin and MET enhances the antitumor effect by inhibiting the growth and invasion as well as inducing apoptosis and autophagy in HCC through PI3K/AKT/mTOR pathway.

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<![CDATA[Identification of prognostic genes in adrenocortical carcinoma microenvironment based on bioinformatic methods]]> https://www.researchpad.co/article/Nb380aed9-3967-4bd6-97cf-f1963b34afc0

Abstract

Background

To identify prognostic genes which were associated with adrenocortical carcinoma (ACC) tumor microenvironment (TME).

Methods and materials

Transcriptome profiles and clinical data of ACC samples were collected from The Cancer Genome Atlas (TCGA) database. We use ESTIMATE (estimation of stromal and Immune cells in malignant tumor tissues using expression data) algorithm to calculate immune scores, stromal scores and estimate scores. Heatmap and volcano plots were applied for differential analysis. Venn plots were used for intersect genes selection. We used protein‐protein interaction (PPI) networks and functional analysis to explore underlying pathways. After performing stepwise regression method and multivariate Cox analysis, we finally screened hub genes associated with ACC TME. We calculated risk scores (RS) for ACC cases based on multivariate Cox results and evaluated the prognostic value of RS shown by receiver operating characteristic curve (ROC). We investigated the association between hub genes with immune infiltrates supported by algorithm from online TIMER database.

Results

Gene expression profiles and clinical data were downloaded from TCGA. Lower immune scores were observed in disease with distant metastasis (DM) and locoregional recurrence (LR) than other cases (P = .0204). Kaplan‐Meier analysis revealed that lower immune scores were significantly associated with poor overall survival (OS) (P = .0495). We screened 1649 differentially expressed genes (DEGs) and 1521 DEGs based on immune scores and stromal scores, respectively. Venn plots helped us find 1122 intersect genes. After analysing by cytoHubba from Cytoscape software, 18 hub genes were found. We calculated RS and ROC showed significantly predictive accuracy (area under curve (AUC) = 0.887). ACC patients with higher RS had worse survival outcomes (P < .0001). Results from TIMER (tumor immune estimation resource) database revealed that HLA‐DOA was significantly related with immune cells infiltration.

Conclusion

We screened a list of TME‐related genes which predict poor survival outcomes in ACC patients from TCGA database.

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