Current Cancer Drug Targets - Volume 24, Issue 2, 2024
Volume 24, Issue 2, 2024
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The Role of LMP1 in Epstein-Barr Virus-associated Gastric Cancer
Authors: Xinqi Huang, Meilan Zhang and Zhiwei ZhangEBV promotes many cancers such as lymphoma, nasopharyngeal carcinoma, and gastric; Latent Membrane Protein 1 (LMP1) is considered to be a major oncogenic protein encoded by Epstein– Barr virus (EBV). LMP1 functions as a carcinogen in lymphoma and nasopharyngeal carcinoma, and LMP1 may also promote gastric cancer. The expression level of LMP1 in host cells is a key determinant in tumorigenesis and maintenance of virus specificity. By promoting cell immortalization and cell transformation, promoting cell proliferation, affecting immunity, and regulating cell apoptosis, LMP1 plays a crucial tumorigenic role in epithelial cancers. However, very little is currently known about LMP1 in Epstein-Barr virus-associated gastric cancer (EBVaGC); the main reason is that the expression level of LMP1 in EBVaGC is comparatively lower than other EBV-encoded proteins, such as The Latent Membrane Protein 2A (LMP2A), Epstein-Barr nuclear antigen 1 (EBNA1) and BamHI-A rightward frame 1 (BARF1), to date, there are few studies related to LMP1 in EBVaGC. Recent studies have demonstrated that LMP1 promotes EBVaGC by affecting The phosphatidylinositol 3-kinase- Akt (PI3K-Akt), Nuclear factor-kappa B (NF-ΚB), and other signaling pathways to regulate many downstream targets such as Forkhead box class O (FOXO), C-X-C-motif chemokine receptor (CXCR), COX-2 (Cyclooxygenase-2); moreover, the gene methylation induced by LMP1 in EBVaGC has become one of the characteristics that distinguish this gastric cancer (GC) from other types of gastric cancer and LMP1 also promotes the formation of the tumor microenvironment (TME) of EBVaGC in several ways. This review synthesizes previous relevant literature, aiming to highlight the latest findings on the mechanism of action of LMP1 in EBVaGC, summarize the function of LMP1 in EBVaGC, lay the theoretical foundation for subsequent new research on LMP1 in EBVaGC, and contribute to the development of novel LMP1-targeted drugs.
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A Comprehensive Review on Current Treatments and Challenges Involved in the Treatment of Ovarian Cancer
Authors: Saika Saman, Nimisha Srivastava, Mohd Yasir and Iti ChauhanOvarian cancer (OC) is the second most common gynaecological malignancy. It typically affects females over the age of 50, and since 75% of cases are only discovered at stage III or IV, this is a sign of a poor diagnosis. Despite intraperitoneal chemotherapy's chemosensitivity, most patients relapse and face death. Early detection is difficult, but treatment is also difficult due to the route of administration, resistance to therapy with recurrence, and the need for precise cancer targeting to minimize cytotoxicity and adverse effects. On the other hand, undergoing debulking surgery becomes challenging, and therapy with many chemotherapeutic medications has manifested resistance, a condition known as multidrug resistance (MDR). Although there are other therapeutic options for ovarian cancer, this article solely focuses on co-delivery techniques, which work via diverse pathways to overcome cancer cell resistance. Different pathways contribute to MDR development in ovarian cancer; however, usually, pump and non-pump mechanisms are involved. Striking cancerous cells from several angles is important to defeat MDR. Nanocarriers are known to bypass the drug efflux pump found on cellular membranes to hit the pump mechanism. Nanocarriers aid in the treatment of ovarian cancer by enhancing the delivery of chemotherapeutic drugs to the tumour sites through passive or active targeting, thereby reducing unfavorable side effects on the healthy tissues. Additionally, the enhanced permeability and retention (EPR) mechanism boosts the bioavailability of the tumour site. To address the shortcomings of conventional delivery, the current review attempts to explain the current conventional treatment with special reference to passively and actively targeted drug delivery systems (DDSs) towards specific receptors developed to treat ovarian cancer. In conclusion, tailored nanocarriers would optimize medication delivery into the intracellular compartment before optimizing intra-tumour distribution. Other novel treatment possibilities for ovarian cancer include tumour vaccines, gene therapy, targeting epigenetic alteration, and biologically targeted compounds. These characteristics might enhance the therapeutic efficacy.
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Overexpression of BRD4 in Gastric Cancer and its Clinical Significance as a Novel Therapeutic Target
Authors: Mengying Zhang, Hong Huang, Meijiao Wei, Mengjia Sun, Guojin Deng, Shuiqing Hu, Hongbo Wang and Yanling GongBackground: BRD4 is a member of the bromodomain and extra terminal domain (BET) family of proteins, containing two bromodomains and one extra terminal domain, and is overexpressed in several human malignancies. However, its expression in gastric cancer has not yet been well illustrated. Objective: This study aimed to elucidate the overexpression of BRD4 in gastric cancer and its clinical significance as a novel therapeutic target. Methods: Fresh gastric cancer tissues and paraffin-embedded specimens of gastric cancer patients were collected, and the BRD4 expression was examined by Western Blot Analysis (WB) and Immunohistochemistry Analysis (IHC), respectively. The possible relationship between BRD4 expression and the clinicopathological features as well as survival in gastric cancer patients was analyzed. The effect of BRD4 silencing on human gastric cancer cell lines was investigated by MTT assay, WB, wound healing assay, and Transwell invasion. Results: The results showed that the expression level in tumor tissues and adjacent tissues was significantly higher than that in normal tissues, respectively (P < 0.01). BRD4 expression level in gastric cancer tissues was strongly correlated with the degree of tumor differentiated degree (P = 0.033), regional lymph nodes metastasis (P = 0.038), clinical staging (P = 0.002), and survival situation (P = 0.000), while the gender (P = 0.564), age (P = 0.926) and infiltrating depth (P = 0.619) of patients were not associated. Increased BRD4 expression resulted in poor overall survival (P = 0.003). In in vitro assays, BRD4 small interfering RNA resulted in significantly decreased BRD4 protein expression, therefore inhibiting proliferation, migration, and invasion of gastric cancer cells. Conclusion: BRD4 might be a novel biomarker for the early diagnosis, prognosis, and therapeutic target in gastric cancer.
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Expression, Prognostic Value, and Immune Infiltration of MTHFD Family in Bladder Cancer
Authors: Bai S. Zheng, Shun De Wang, Jun Yong Zhang and Cheng Guo GeBackground: The Methylenetetrahydrofolate Dehydrogenase (MTHFD) family plays an important role in the development and prognosis of a variety of tumors; however, the role of the MTHFD family in bladder cancer is unclear. Methods: R software, cBioPortal, GeneMANIA, and online sites such as String-LinkedOmics were used for bioinformatics analysis. Results: MTHFD1/1L/2 was significantly upregulated in bladder cancer tissues compared with normal tissues, high expression of the MTHFD family was strongly associated with poorer clinical grading and staging, and bladder cancer patients with upregulated expression of MTHFD1L/2 had a significantly worse prognosis. Gene function and PPI network analysis revealed that the MTHFD family and related genes play synergistic roles in the development of bladder cancer. 800 co-expressed genes related to the MTHFD family were used for functional enrichment analysis, and the results showed that many genes were associated with various oncogenic pathways such as cell cycle and DNA replication. More importantly, the MTHFD family was closely associated with multiple infiltrating immune lymphocytes, including Treg cells, and immune molecules such as TNFSF9, CD274, and PDCD1. Conclusion: Our study shows that MTHFD family genes may be potential prognostic markers and therapeutic targets for patients with bladder cancer.
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PIWIL1 Promotes Malignant Progression of Papillary Thyroid Carcinoma by Inducing EVA1A Expression
Authors: Lianyong Liu, Fengying Wu, Xiaoying Zhang and Xiangqi LiIntroduction: Papillary thyroid carcinoma (PTC) is the most common subtype of thyroid cancer. Previous studies have reported on the ectopic expression of P-element-induced wimpy testis ligand 1 (PIWIL1) in various human cancers, but its role in PTC progression has not been investigated. Methods: In this study, we measured the expression levels of PIWIL1 and Eva-1 homolog A (EVA1A) in PTC using qPCR and WB. We performed a viability assay to evaluate PTC cell proliferation and used flow cytometry to investigate apoptosis. Moreover, we conducted a Transwell invasion assay to quantify cell invasion and assessed PTC growth in vivo using xenograft tumor models. Results: Our findings showed PIWIL1 to be highly expressed in PTC and promote cell proliferation, cell cycle activity, and cell invasion, while suppressing apoptosis. Additionally, PIWIL1 accelerated tumor growth in PTC xenografts by modulating the EVA1A expression. Conclusion: Our study suggests that PIWIL1 contributes to the progression of PTC through EVA1A signaling, indicating its potential role as a therapeutic target for PTC. These results provide valuable insights into PIWIL1 function and may lead to more effective treatments for PTC.
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UCA1 Inhibits NKG2D-mediated Cytotoxicity of NK Cells to Breast Cancer
Authors: Jun-Yi Yin, Yao Zhou, Xiao-Ming Ding, Run-Ze Gong, Yan Zhou, Hai-Yan Hu, Yuan Liu, Xiao-Bin Lv and Bing ZhangBackground: Natural killer cells play important roles in tumor immune surveillance, and cancer cells must resist this surveillance in order to progress and metastasise. Introduction: The study aimed to explore the mechanism of how breast cancer cells become resistant to the cytotoxicity of NK cells. Methods: We established NK-resistant breast cancer cells by exposing MDA-MB-231 cells and MCF-7 cells to NK92 cells. Profiles of lncRNA were compared between the NK-resistant and parental cell lines. Primary NK cells were isolated by MACS, and the NK attacking effect was tested by non-radioactive cytotoxicity. The change in lncRNAs was analyzed by Gene-chip. The interaction between lncRNA and miRNA was displayed by Luciferase assay. The regulation of the gene was verified by QRT-PCR and WB. The clinical indicators were detected by ISH, IH, and ELISA, respectively. Results: UCA1 was found to be significantly up-regulated in both NK-resistant cell lines, and we confirmed such up-regulation on its own to be sufficient to render parental cell lines resistant to NK92 cells. We found that UCA1 up-regulated ULBP2 via the transcription factor CREB1, while it up-regulated ADAM17 by “sponging” the miR-26b-5p. ADAM17 facilitated the shedding of soluble ULBP2 from the surface of breast cancer cells, rendering them resistant to killing by NK cells. UCA1, ADAM17, and ULBP2 were found to be expressed at higher levels in bone metastases of breast cancer than in primary tumors. Conclusion: Our data strongly suggest that UCA1 up-regulates ULBP2 expression and shedding, rendering breast cancer cells resistant to killing by NK cells.
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AHNAK2 Promotes the Progression of Differentiated Thyroid Cancer through PI3K/AKT Signaling Pathway
Authors: Min Xu, Jialiang Wen, Qiding Xu, Huihui Li, Bangyi Lin, Adheesh Bhandari and Jinmiao QuAims: AHNAK2 may be used as a candidate marker for TC diagnosis and treatment. Background: Thyroid cancer (TC) is the most frequent malignancy in endocrine carcinoma, and the incidence has been increasing for decades. Objective: To understand the molecular mechanism of DTC, we performed next-generation sequencing (NGS) on 79 paired DTC tissues and normal thyroid tissues. The RNA-sequencing (RNA-seq) data analysis results indicated that AHNAK nucleoprotein 2 (AHNAK2) was significantly upregulated in the thyroid cancer patient’s tissue. Methods: We also analyzed AHNAK2 mRNA levels of DTC tissues and normal tissues from The Cancer Genome Atlas (TCGA). The association between the expression level of AHNAK2 and clinicopathological features was evaluated in the TCGA cohort. Furthermore, AHNAK2 gene expression was analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) in 40 paired DTC tissues and adjacent normal thyroid tissues. The receiver operating characteristic (ROC) curve was performed to evaluate the diagnostic value of AHNAK2. For cell experiments in vitro, AHNAK2 was knocked down using small interfering RNA (siRNA), and the biological function of AHNAK2 in TC cell lines was investigated. The expression of AHNAK2 was significantly upregulated in both the TCGA cohort and the local cohort. Results: The analysis results of the TCGA cohort indicated that the upregulation of AHNAK2 was associated with tumor size (P < 0.001), lymph node metastasis (P < 0.001), and disease stage (P < 0.001). The area under the curve (AUC, TCGA: P < 0.0001; local validated cohort: P < 0.0001) in the ROC curve revealed that AHNAK2 might be considered a diagnostic biomarker for TC. The knockdown of AHNAK2 reduced TC cell proliferation, colony formation, migration, invasion, cell cycle, and induced cell apoptosis. Conclusion: Furthermore, the protein levels of phospho-PI3 Kinase p85 and phospho-AKT were downregulated in the transfected TC cell. Our study results indicate that AHNAK2 may promote metastasis and proliferation of thyroid cancer through PI3K/AKT signaling pathway. Thus, AHNAK2 may be used as a candidate marker for TC diagnosis and treatment.
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Volumes & issues
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Volume 25 (2025)
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Volume 24 (2024)
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Volume 23 (2023)
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Volume 22 (2022)
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Volume 21 (2021)
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Volume 20 (2020)
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Volume 19 (2019)
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Volume 18 (2018)
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Volume 17 (2017)
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Volume 16 (2016)
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Volume 15 (2015)
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Volume 14 (2014)
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Volume 13 (2013)
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Volume 12 (2012)
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Volume 11 (2011)
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Volume 10 (2010)
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Volume 9 (2009)
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Volume 8 (2008)
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Volume 7 (2007)
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Volume 6 (2006)
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Volume 5 (2005)
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Volume 4 (2004)
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Volume 3 (2003)
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Volume 2 (2002)
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Volume 1 (2001)
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