Nasopharyngeal carcinoma is a metastatic malignant tumor originating from nasopharyngeal epithelium. Lacking or nonspecific symptoms of patients with early stage nasopharyngeal carcinoma have significantly reduced the accuracy of diagnosing and predicting nasopharyngeal carcinoma development. This study aimed to identify gene signatures of nasopharyngeal carcinoma and uncover potential mechanisms. Two gene expression profiles (GSE12452 and GSE13597) containing 56 nasopharyngeal carcinoma samples and 13 normal control samples were analyzed to identify the differentially expressed genes. In total, 179 up-regulated genes and 238 down-regulated genes were identified. Functional and pathway enrichment analysis showed that up-regulated genes were significantly involved in cell cycle, oocyte meiosis, DNA replication and p53 signaling pathway, while down-regulated genes were enriched in Huntington's disease,metabolic pathways. Subsequently, the top 10 hub genes, TOP2A (topoisomerase (DNA) II alpha), CDK1 (cyclin-dependent kinase 1), CCNB1 (cyclin B1), PCNA (proliferating cell nuclear antigen), MAD2L1 (mitotic arrest deficient 2 like 1), BUB1 (budding uninhibited by benzimidazoles 1 homolog), CCNB2 (cyclin B2), AURKA (aurora kinase A), CCNA2 (cyclin A2), CDC6 (cell division cycle 6 homolog), were identified from protein-protein interaction network. Furthermore, Module analysis revealed that the ten hub genes except TOP2A were belonged to module 1, indicating the upregulation of these hub genes associated molecular pathways in nasopharyngeal carcinoma might activate nasopharyngeal carcinoma pathogenesis. In conclusion, this study indicated that the identified differentially expressed genes and hub genes enrich our understanding of the molecular mechanisms of nasopharyngeal carcinoma, which could eventually translate into additional biomarkers to facilitate the early diagnosis and therapeutic approaches.
BackgroundHuman interacting protein X1 (PinX1) has been identified as a critical telomerase inhibitor and proposed to be a putative tumor suppressor gene. Loss of PinX1 has been found in a large variety of malignancies, however, its function in inhibiting telomerase activity of tumor cells is not well documented. Here we show that PinX1 is essential for down-regulation telomerase activity of nasopharyngeal carcinoma.MethodsExpression vectors of human PinX1 (pEGFP-C3-PinX1) and its small interfering RNA (PinX1-FAM-siRNA) were constructed and transfected into NPC. Their effects on mRNA of telomerase catalytic subunit (hTERT), telomerase activity, cell proliferation, cell migration, wound healing, cell cycles and apoptosis were examined using semi-quantitative RT-PCR, stretch PCR, MTT assay, Transwell, scratch assay and flow cytometry, respectively.ResultsTransfection of pEGFP-C3-PinX1 and PinX1-FAM-siRNA increased and reduced PinX1 mRNA by 1.6-fold and 70%, respectively. Over-expression of PinX1 decreased hTERT mRNA by 21%, reduced telomerase activity, inhibited cell growth, migration and wound healing ability, arrested cells in G0/G1 phase, and increased apoptotic index. In contrast, down-regulation of PinX1 did not alter the above characteristics.ConclusionsPinX1 may play important roles in NPC proliferation, migration and apoptosis and has application potential in tumor-targeted gene therapy.
One of the main clinical treatments for advanced nasopharyngeal carcinoma is chemotherapy, but systemic administration can cause serious adverse reactions. New type of nanomaterial which can actively targeting, imaging, and treating nasopharyngeal carcinoma at the same time to enhance the effect of chemotherapy, meanwhile monitoring the intracellular drug release process at the level of single cancer cell was urgently needed. GE11, an EGFR antagonist peptide, was used to target nasopharyngeal carcinoma which has positive expression of EGFR on its nucleus. GE11‐modified graphene quantum dots (GQDs@GE11) were used as drug carriers for clinical chemotherapeutics cisplatin (CDDP) and doxorubicin (DOX). The emission spectrum of GQDs (460 nm) and the excitation spectrum of DOX (470 nm) have a good overlap, thus the transfer and release process of DOX can be sensitively detected by the fluorescence resonance energy transfer (FRET). CDDP was used to enhance the chemotherapy effect of nanoprobe, and the loading amount of DOX and CDDP on GQDs@GE11 nanoprobe were up to 67 and 50 mg/g, respectively. In vivo experiments have confirmed that GQDs@GE11/CDDP/DOX nanoprobe can be enriched to tumor site through specific targeting effect, and significantly inhibit tumor cell proliferation. This new type of targeted therapy fluorescent probe provides new ideas for the study of drug release process and the treatment of nasopharyngeal carcinoma.
Background/Aims: Cancer stem cells (CSCs) are important factors for the continuous growth, recurrence, and metastasis of malignant tumors. They are responsible for the ineffectiveness of traditional radiotherapy and chemotherapy toward malignant tumors. Currently, stem cells or side-population cells have been isolated from many cancer cell lines and malignant tumor tissues, including nasopharyngeal carcinoma. Exploring the biological characteristics of CSCs for CSC-targeted therapy has gained importance. CSCs possess higher telomerase activity; thus, the use of the gene encoding telomerase inhibitor PinX1 gene to target telomerase in CSCs and inhibit proliferation, invasion, and metastasis of CSCs has become an important means for the treatment of malignant tumors. PinX1 may regulate complex pathways, including TRF1, Mad1/c-Myc, and p53. Methods: In this study, nasopharyngeal CD133+ CSCs were sorted using CD133 immunomagnetic beads by flow cytometry The successful isolation of CD133+ CSCs was confirmed by examining their surface markers, namely CD44, NaNOG, and SOX2 as well as their ability to undergo in vivo tumorigenesis and in vitro sphere formation, proliferation, migration, and invasion. In addition, CD133+ CSCs were transfected with the constructed PinX1 overexpression plasmid or siRNA and the resulting effects on their proliferation, migration, invasion, and apoptosis were detected using cell counting kit-8 (CCK-8), transwell assay, and scratch test, respectively. Furthermore, their effects on mRNA and protein levels of TRF1, TRF2, Mad1, c-Myc, and p53 were examined using quantitative real-time PCR and western blot, respectively. Results: The overexpression of PinX1 in CD133+ CSCs significantly decreased hTERT (P < 0.001), inhibited proliferation, migration, and invasion, induced apoptosis, and significantly decreased c-Myc mRNA levels (P < 0.001), while it increased TRF1, Mad1, and p53 mRNA levels (all P < 0.001). On the other hand, PinX1 silencing in CD133+ CSCs significantly decreased TRF1, Mad1, and p53 mRNA levels (all P < 0.01), while it increased hTERT and c-Myc mRNA levels (all P < 0.05). Conclusion: These results indicate that PinX1 downregulates telomerase activity in CD133+ CSCs, inhibits its proliferation, migration, and invasion, and induces apoptosis possibly through TRF1, Mad1/c-Myc, and p53–mediated pathways.
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