Agmatinase promotes the lung adenocarcinoma tumorigenesis by activating the NO-MAPKs-PI3K/Akt pathway.
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ABSTRACT:
SUBMITTER: Zhu HE
PROVIDER: S-EPMC6838094 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Despite considerable recent advancements in colorectal cancer (CRC) therapy, the prognosis of patients with advanced disease remains poor. Further understanding of the molecular mechanisms and treatment strategies of this disease is required. Zinc finger protein 692 (ZNF692), also known as AREBP and Zfp692, was first reported to have an important role in gluconeogenesis. A recent study demonstrated that ZNF692 is overexpressed in lung adenocarcinoma (LUAD) tissues and that ZNF692 knockdown inhibited LUAD cell proliferation, migration, and invasion both in vitro and in vivo. However, the role of ZNF692 in colon adenocarcinoma (COAD) remains unclear. The present study revealed that ZNF692 was upregulated in COAD tissues and cells and that high ZNF692 expression was significantly correlated with lymph node metastasis, distant metastasis and tumor stage in COAD patients. Gain‑ and loss‑of‑function experiments were employed to identify the function of ZNF692 in COAD progression. In vitro and in vivo assays revealed that ZNF692 promoted COAD cell proliferation, migration and invasion. Furthermore, western blot analysis demonstrated that the effects of ZNF692 were mediated by upregulating cyclin D1, cyclin‑dependent kinase 2 (CDK2) and matrix metalloproteinase‑9 (MMP‑9) and by downregulating p27Kip1 through the phosphoinositide 3‑kinase/AKT signaling pathway. Collectively, these data indicated that ZNF692 may serve as a novel oncogene and a potential treatment target in COAD patients.
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Project description:SCL/TAL1 interrupting locus (STIL) regulates centriole replication and causes chromosome instability, which is closely related to malignant tumors. The purpose of our study was to investigate the role of STIL in bladder cancer (BC) tumorigenesis for the first time. The public database indicated that STIL is highly expressed and correlated with the cell cycle in BC. Immunohistochemistry staining showed that STIL expression is significantly elevated in BC tissues compared with paracancer tissues. CRISPR-Cas9 gene editing technology was used to induce BC cells to express STIL-specific sgRNA, revealing a significantly delayed growth rate in STIL knockout BC cells. Moreover, cell cycle arrest in the G0/G1 phase was triggered by decreasing STIL, which led to delayed BC cell growth in vitro and in vivo. Mechanically, STIL knockout inhibited the PI3K/AKT/mTOR pathway and down-regulated the expression of c-myc. Furthermore, SC79 (AKT activating agent) partially reversed the inhibitory effects of STIL knockout on the proliferation and migration of BC cells. In conclusion, STIL enhanced the PI3K/AKT/mTOR pathway, resulting in increased expression of c-myc, ultimately promoting BC occurrence and progression. These results indicate that STIL might be a potential target for BC patients.
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Project description:BACKGROUND:Brain metastasis (BM) is associated with poor prognosis, recurrence, and death in patients with non-small cell lung cancer (NSCLC). Lysophosphatidylcholine acyltransferase 1 (LPCAT1) has been reported to be involved in the progression, metastasis and recurrence of malignancies. However, the potential role of LPCAT1 in NSCLC remains poorly understood. This study was aimed to identify genes involved in lung adenocarcinoma (LUAD) brain metastasis, and look into the role of LPCAT1 in LUAD progression. METHODS:We used integrative genomic analysis to identify genes involved in lung adenocarcinomas. LPCAT1 expression was evaluated in tumor tissues from LUAD patients and LUAD cell lines. The role of LPCAT1 was subsequently investigated both in vitro and in vivo. The mechanism underlying the involvement of LPCAT1 in LUAD progression was explored with the activator of PI3K/AKT pathway. RNA sequencing was performed to confirm the involvement of LPCAT1 and associated pathway in LUAD brain metastasis. RESULTS:LPCAT1 was up-regulated in LUAD tissues and cell lines. shRNA-mediated depletion of LPCAT1 not only abrogated cell proliferation, migration and invasion in vitro, but also arrested tumor growth and brain metastases in vivo. Notably, LPCAT1 at least partially influenced LUAD progression through PI3K/AKT signal pathway by targeting MYC transcription. Moreover, expression of LPCAT1 was higher in tissues of LUAD patients with BM than those without BM as revealed by IHC staining, RNA-Sequencing and qPCR analysis. Finally, elevated LPCAT1 expression in patients with lung adenocarcinomas was associated with a poor clinical outcome. CONCLUSIONS:This study showed that LPCAT1 works as a regulator of cell metastasis and may serve as a novel therapeutic target for BM in lung adenocarcinoma.
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Project description:ObjectsThe family with sequence similarity 83B (FAM83B) is one of the markers for poor prognosis in several carcinomas, but the expression and the mechanism resulted in malignant phenotype in lung adenocarcinoma (LUAD) remain to be elucidated.Methods Data of RNA-seq in LUAD were downloaded from the cancer genome atlas (TCGA) database for differential expression and survival analysis, and immunohistochemistry was employed to analyze the protein expression of FAM83B in 126 cases of primary LUAD. The LUAD cell lines were collected for the detection of the effects on migration and invasion. Then, western blot was performed to measure the expression of tissue inhibitor of metalloproteinase (TIMP)-1 and activation of PI3K/AKT/NF-κB pathway.ResultsFAM83B was overexpressed in multiple types of carcinomas; The differential expression analysis revealed that the level of FAM83B was higher in LUAD than that in para-carcinoma; The patients with overexpression of FAM83B were with shorter overall survival (OS), disease specific survival (DSS) and progress free interval (PFI); Enrichment analysis suggested it was related to the focal adhesion of LUAD. Immunohistochemistry analysis demonstrated that higher FAM83B expression was positively related to lymph node metastasis in primary. Scratch assay and Borden chamber assay showed that the overexpression of FAM83B promoted migration and invasion activity in vitro. Furthermore, high level of FAM83B accelerated the tumorigenesis in vivo. Western blot showed that TIMP-1 was upregulated in H1299/FAM83B OE cells accompanying by the activation of PI3K/AKT/NF-κB pathway.ConclusionsFAM83B was a marker for poor prognosis of LUAD and it might promote the expression of TIMP-1 by activating PI3K/AKT/NF-κB pathway and then affect the ECM balance, which resulted in the migration and invasion of LUAD.
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Project description:RING finger protein-7 (RNF7) functions as a positive regulator in the progression of multiple malignancies. However, the underlying mechanism by which RNF7 contributes to pancreatic cancer (PC) is lacking. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to test the level of RNF7expression in PC cell lines and tissues. The role of RNF7 in PC tumorigenesis was analyzed by Cell Counting Kit-8 (CCK-8). 5-Ethynyl-20-deoxyuridine (EdU), wound-healing/Transwell assays, as well as a subcutaneous tumorigenesis model were constructed to assess the role of RNF7 in PC cells. The association between RNF7 and PI3K/Akt signaling were assessed by western blot and further confirmed by rescue experiments. The PC patients with upregulated expression of RNF7 had poor survival. Overexpression of RNF7 significantly facilitated PC proliferative and migrative and invasive properties in vitro and vivo; however, knockdown of RNF7exhibited the opposite results. Mechanistically, RNF7 promoted PANC-1 and SW1990 cell growth through impacting the activation of the PI3K/Akt signaling pathway. Our data demonstrated that RNF7 promoted PC tumorigenesis via activating the PI3K/Akt signaling pathway and might be regarded as one of the potential therapies to PC.
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Project description:A limited number of studies have indicated an association between isoleucyl-tRNA synthetase 2 (IARS2) and tumorigenesis. We evaluated IARS2 protein expression in lung tumor tissues and paired non-tumor tissues. We found higher IARS2 expression in the tumor tissues, which was associated with the late Tumor and Node stages of the Tumor, Node, Metastasis staging system. Silencing IARS2 inhibited the activity of A549 and H1299 cells, resulting in G0/G1 stasis of A549 cells and mitochondrial apoptosis. IARS2 silencing was also found to inhibit NSCLC tumor growth in nude mice. Complementary DNA microarray analysis revealed 742 differentially expressed genes (507 upregulated and 235 downregulated) in IARS2-silenced A549 cells compared to controls. Ingenuity Pathway Analysis of the differential expression data suggested that multiple pathways are associated with IARS2 silencing in NSCLC cells; upstream analysis predicted the activation or inhibition of transcriptional regulators. Correlation analysis revealed that AKT and MTOR activities were significantly inhibited in IARS2-silenced cells, but were partially restored by the AKT-stimulating agent SC79. IARS2 appears to regulate lung cancer cell proliferation via the AKT/MTOR pathway. Our results help clarify the complex roles of IARS2 in tumorigenesis and suggest that it may be a novel regulator of lung cancer development.
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Project description:BackgroundAging disturbs the skin morphology and function, manifested as thinned epithelium and impaired wound healing. As a major type of skin cells, epidermal stem cells (EpiSCs) are inevitably affected by aging. The effect of age on EpiSCs and wound healing needs to be further explored.MethodsSkin RNA-seq data of young (5 months) and old (30 months) CB6F1 mice were obtained from GEO Series GSE35322 with 10 in each age group. Differentially expressed genes were analyzed, and EpiSCs-related pathways were enriched by KEGG. The age-related changes of the screened PI3K/Akt pathway were validated by Western Blot and immunofluorescence of epidermis of SD rats (2, 17, and 23 months, n = 6). The expression of upstream protein EGFR was assessed by immunofluorescence in skin of mice (4, 13, and 23 months, n = 6) and human (respectively, 23, 28, 30 years old in the young group and 69, 73, 78 years old in the old group) skin. Inhibitors of EGFR were used to verify its effects on EpiSCs and wound healing. The small molecule drug Tideglusib was tested for its effects on signaling pathways of EpiSCs and wound healing of aged rats. Western Blot was used for the detection of signaling pathways in in vitro experiments. Cell migration assays were used to assess cell migration ability. Flow cytometry was used to detect changes in cell cycle and apoptosis levels. Sulforhodamine B assay and CCK-8 assay were used to evaluate cell proliferation and viability, respectively. Student's t test and one-way analysis of variance (ANOVA) followed by the multiple comparisons Bonferroni test were used for statistical analysis. The 0.05 level of confidence was accepted as a significant difference.ResultsEpiSCs-related PI3K/Akt pathway was enriched by KEGG and verified by decreased phosphorylation of Akt (32.1 ± 13.8%, P < 0.01) and mTOR (38.9 ± 11.8%, P < 0.01) in aged epidermis of rats. Furthermore, the expression of PI3K/Akt-upstream EGFR decreased with age in the epidermis of mouse (27.6 ± 5.5%, P < 0.01) and human (25.8 ± 9.3%, P < 0.01). With EGFR blocked by Erlotinib, EpiSCs showed reduced phosphorylation of Akt (30.4 ± 10.6%, P < 0.01) and mTOR (39.8 ± 12.8%, P < 0.01), impaired proliferation and migration after incubated for 24 h and 36 h (P < 0.05), and higher levels of apoptosis (11.9 ± 1.7%, P < 0.05), and rats showed slower wound healing from d7 to d14 after wounding (P < 0.01). In addition to slower wound healing rates, aged rats also showed a decrease in the efficacy of EGF, partly due to the downregulated EGFR expression. By activating PI3K/Akt pathway, Tideglusib promoted the proliferation and migration of EpiSCs with apoptosis inhibited (P < 0.01) and accelerated wound healing in aged rats from d7 to d14 after wounding (P < 0.05). Notably, the combined use of Tideglusib and EGF could further enhance wound healing in aged rats.ConclusionsThe decreased expression of EGFR in epidermis with age resulted in decreased activity of the PI3K/Akt pathway and limited EGF efficacy. Tideglusib could assist wound healing in aged rats via activating PI3K/Akt pathway, which may be considered as an ingredient for medical and cosmetics use.
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Project description:Although MRPS16 is involved in cancer development, its mechanisms in developing LAUD remain unclear. Herein, qRT-PCR, WB and IHC were utilized for evaluating MRPS16 expression levels, while functional assays besides animal experiments were performed to measure MRPS16 effect on LAUD progression. Using WB, the MRPS16 effect on PI3K/AKT/Frataxin signalling pathway was tested. According to our study, MRPS16 was upregulated in LAUD and was correlated to the advanced TNM stage as well as poor clinical outcomes, which represent an independent prognostic factor. Based on functional assays, MRPS16 is involved in promoting LAUD growth, migration and invasion, which was validated further in subsequent analyses through PI3K/AKT/Frataxin pathway activation. Moreover, MRPS16-knockdown-mediated Frataxin overexpression was shown to restore the reduction in tumour cells proliferation, migration and invasion. Our results revealed that MRPS16 caused an aggressive phenotype to LAUD and was a poor prognosticator; thus, targeting MRPS16 may be effectual in LAUD treatment.
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Project description:Ubiquitin-associated protein 2-like (UBAP2L) is highly expressed in various types of tumors and has been shown to participate in tumor growth and metastasis; however, its role in gastric cancer (GC) remains unknown. In this study, we observed that UBAP2L expression was markedly elevated in GC tissues and five GC cell lines. Higher expression of UBAP2L was associated with poor prognosis as revealed by bioinformatics analysis on online websites and laboratory experiments. Knockdown of UBAP2L impeded the migration and invasion abilities of GC cell lines. In contrast, its overexpression enhanced the migration and invasion abilities of GC cell lines. Overexpression of UBAP2L also increased the number and size of lung metastatic nodules in vivo. According to the results of mass spectrometry and pathway annotation of the identified proteins, the PI3K/AKT pathway was found to be related to UBAP2L regulation. Further exploration and rescue experiments revealed that UBAP2L stimulates the expression and nuclear aggregation of p65 and promotes the expression of SP1 by activating the PI3K/AKT pathway. In summary, our findings indicate that UBAP2L regulates GC metastasis through the PI3K/AKT/SP1/NF-κB axis. Thus, targeting UBAP2L may be a potential therapeutic strategy for GC.
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