Cellular Oncology最新文献

Background: Gastric cancer (GC) ranks as the fourth leading cause of cancer-related deaths worldwide, with most patients diagnosed at advanced stages due to the absence of reliable early detection biomarkers.

Methods: RNA-sequencing was conducted to identify the differentially expressed genes between GC tissues and adjacent normal tissues. CCK8, EdU, colony formation, transwell, flow cytometry and xenograft assays were adopted to explore the biological function of ZBTB10 and betulinic acid (BA) in GC progression. RNA-sequencing and phospho-proteomic profiling were performed to analyze the signaling pathways associated with ZBTB10-inhibiting GC progression. Chromatin immunoprecipitation, Co-immunoprecipitation and luciferase reporter assay were employed to elucidate the potential molecular regulatory mechanisms of ZBTB10 in GC.

Results: ZBTB10 was one of the most significantly downregulated genes in GC tissues, and higher expression levels of ZBTB10 was correlated with better prognosis in patients with GC. Functional studies revealed that ZBTB10 overexpression and BA inhibited GC progression both in vitro and in vivo. Mechanistically, ZBTB10 enhanced ARRDC3 expression by binding to a specific response element in the ARRDC3 promoter region. Elevated ARRDC3 then directly interacted with β-4 integrin (ITGB4), leading to its ubiquitination and degradation. This cascade ultimately resulted in the downregulation of PI3K and AKT phosphorylation level. Moreover, ZBTB10 was a key target for BA in GC and BA inhibited GC progression through regulating the ZBTB10/ARRDC3/ITGB4/PI3K/AKT axis.

Conclusions: Our findings reveal that BA holds promise as an effective therapeutic strategy for GC, and the ZBTB10/ARRDC3/ITGB4/PI3K/AKT axis may serve as a novel diagnostic and therapeutic target.

Background: Sorafenib is a commonly used first-line kinase-targeted drug for advanced hepatocellular carcinoma (HCC) patients suffering from limited efficacy. Emerging evidence indicates that sorafenib exerts anti-cancer activity through the induction of ferroptosis in HCC cells, but the underlying mechanism is still unclear.

Methods: The whole transcriptome sequencing and bioinformatics analysis were used to screen for target genes. The expression and subcellular localization of regulatory factor X1 (RFX1) were determined through immunohistochemistry, immunofluorescence, PCR and western blot analyses. The impact of RFX1 on HCC cell growth was assessed using CCK8, colony formation assays, cell death assays, and animal experiments. Glutathione measurement, iron assay and lipid peroxidation detection assays were performed to investigate ferroptosis of HCC cells. The regulatory mechanism of RFX1 in HCC was investigated by sgRFX1, co-IP, ChIP and luciferase experiments. Immunohistochemical and survival analyses were performed to examine the prognostic significance of RFX1 in HCC.

Results: In this study, we found that RFX1 promote ferroptosis in HCC cells. Further, we showed that sorafenib induces cell death through RFX1-mediated ferroptosis in HCC cells. The enhancing effect of RFX1 on HCC cell ferroptosis is largely dependent on inhibition of cystine/glutamate antiporter (system Xc-) activity through the BECN-SLC7A11 axis, where RFX1 directly binds to the promoter region of BECN1 and upregulates BECN1 expression. In addition, a STAT3-RFX1-BECN1 signalling loop was found to promote RFX1 expression in HCC cells.

Conclusions: Our study reveals a novel mechanism underlying sorafenib-induced HCC cell death.

Cell senescence is a natural response within our organisms. Initially, it was considered an effective anti-tumor mechanism. However, it is now believed that while cell senescence initially acts as a robust barrier against tumor initiation, the subsequent accumulation of senescent cells can paradoxically promote cancer recurrence and cause damage to neighboring tissues. This intricate balance between cell proliferation and senescence plays a pivotal role in maintaining tissue homeostasis. Moreover, senescence cells secrete many bioactive molecules collectively termed the senescence-associated secretory phenotype (SASP), which can induce chronic inflammation, alter tissue architecture, and promote tumorigenesis through paracrine signaling. Among the myriads of compounds, senotherapeutic drugs have emerged as exceptionally promising candidates in anticancer treatment. Their ability to selectively target senescent cells while sparing healthy tissues represents a paradigm shift in therapeutic intervention, offering new avenues for personalized oncology medicine. Senolytics have introduced new therapeutic possibilities by enabling the targeted removal of senescent cells. As standalone agents, they can clear tumor cells in a senescent state and, when combined with chemo- or radiotherapy, eliminate residual senescent cancer cells after treatment. This dual approach allows for the intentional use of lower-dose therapies or the removal of unintended senescent cells post-treatment. Additionally, by targeting non-cancerous senescent cells, senolytics may help reduce tumor formation risk, limit recurrence, and slow disease progression. This article examines the mechanisms of cellular senescence, its role in cancer treatment, and the importance of senotherapy, with particular attention to the therapeutic potential of senolytic drugs.

Background: Hepatocellular carcinoma (HCC) remains a significant global health challenge with limited treatment options. Lenvatinib, a tyrosine kinase inhibitor, has shown promise but is often undermined by the development of drug resistance.

Methods: Utilizing high-throughput sequencing, we investigated the molecular mechanisms underlying lenvatinib resistance in HCC cells, with a focus on metabolic pathways. Key genes, including GALNT6, were validated through quantitative real-time PCR. The effects of GALNT6 knockdown on lenvatinib sensitivity were examined in vitro and in vivo. O-GalNAc glycosylation was assessed using Vicia Villosa Lectin. Immune cell infiltration and interactions were analyzed in the TCGA-LIHC cohort, with further validation by Western blotting and immunohistochemistry.

Results: Our findings indicate that lenvatinib resistance in HCC is driven by the mucin-type O-glycosylation pathway, with GALNT6 playing a critical role. Knockdown of GALNT6 led to reduced O-GalNAc glycosylation, including the modification of LAPTM5, resulting in decreased LAPTM5 activity and autophagy inhibition. Additionally, GALNT6 silencing disrupted the PDGFA-PDGFRB axis, impairing the activation of cancer-associated fibroblasts (CAFs) and reducing their secretion of SPP1, which collectively diminished lenvatinib resistance.

Conclusions: GALNT6 is integral to the resistance mechanisms against lenvatinib in HCC by modulating autophagy and CAF activation. Targeting GALNT6 offers a promising strategy to enhance lenvatinib efficacy and improve therapeutic outcomes in HCC.

Purpose: Clarification of cisplatin resistance may provide new targets for therapy in cisplatin resistant ovarian cancer. The current study aims to explore involvement of isoforms of AU-rich element RNA-binding protein 1 (AUF1) in cisplatin resistance in ovarian cancer.

Methods: The cancer stem cell-like features were analyzed using colony formation assay, tumor sphere formation assay and nude mouse xenograft experiments. AUF1 isoforms expression was analyzed using immunoblotting, qRT-PCR, and immunohistochemistry. RIP and Biotin pulldown was used to analyze the interaction of SRSF2 and hnRNPA1 with AUF1 transcript. Transcriptome regulated by AUF1 isoforms was analyzed by RNA-seq.

Results: The current study demonstrated differential expression of AUF1 isoforms in cisplatin sensitive and resistant ovarian cancer tissues and cells. P37 isoform promoted proliferation, while p45 isoform enhanced responsiveness of ovarian cancer cells to cisplatin. the clonal formation capacity of the cells, and the restoration of p45 expression reduced the capacity with cisplatin treatment. The competitive binding of phosphorylated hnRNPA1 and O-GlcNAc-modified SRSF2 on AUF1 exon 2 and exon 7 regulated the alternative splicing of AUF1.

Conclusion: The competitive binding of phosphorylated hnRNPA1 and O-GlcNAc modified SRSF2 on exon 2 and exon 7 regulated the alternative splicing of AUF1 and subsequent isoform expression. P37 isoform played a "cancer promoter" role, p42 and p45, especially p45 played a "cancer suppressor" role in ovarian cancer. This study provides a new target for exploring the drug resistance mechanism of ovarian cancer.

Background: The most common type of lung cancer is non-small cell lung cancer (NSCLC), accounting for 85% of all cases. Programmed cell death (PCD), an important regulatory mechanism for cell survival and homeostasis, has become increasingly prominent in cancer research in recent years. As such, exploring the role of PCD in NSCLC may help uncover new mechanisms for therapeutic targets.

Methods: We utilized the GEO database and TCGA NSCLC gene data to screen for co-expressed genes. To delve deeper, single-cell sequencing combined with spatial transcriptomics was employed to study the intrinsic mechanisms of programmed cell death in cells and their interaction with the tumor microenvironment. Furthermore, Mendelian randomization was applied to screen for causally related genes. Prognostic models were constructed using various machine learning algorithms, and multi-cohort multi-omics analyses were conducted to screen for genes. In vitro experiments were then carried out to reveal the biological functions of the genes and their relationship with apoptosis.

Results: Cells with high programmed cell death activity primarily activate pathways related to apoptosis, cell migration, and hypoxia, while also exhibiting strong interactions with smooth muscle cells in the tumor microenvironment. Based on a set of programmed cell death genes, the prognostic model NSCLCPCD demonstrates strong predictive capabilities. Moreover, laboratory experiments confirm that SLC7A5 promotes the proliferation of NSCLC cells, and the knockout of SLC7A5 significantly increases tumor cell apoptosis.

Conclusions: Our data indicate that programmed cell death is predominantly associated with pathways related to apoptosis, tumor metastasis, and hypoxia. Additionally, it suggests that SLC7A5 is a significant risk indicator for the prognosis of non-small cell lung cancer (NSCLC) and may serve as an effective target for enhancing apoptosis in NSCLC tumor cells.

BRCA1 (Breast Cancer 1) is a tumor suppressor gene with a role in DNA repair by Homologous Recombination (HR), and maintenance of genomic stability that is frequently investigated in breast, prostate, and ovarian cancers. BRCA1 mutations or dysregulation in glioblastoma can lead to impaired DNA repair mechanisms, resulting in tumor progression and resistance to standard therapies. Several studies have shown that BRCA1 expression is altered, albeit rarely, in glioblastoma, leading to poor prognosis and increased tumor aggressiveness. In addition, the communication of BRCA1 with other molecular pathways such as p53 and PTEN further complicates its role in glioblastoma pathogenesis. Targeting BRCA1-related pathways in these cases has shown the potential to improve the efficacy of standard treatments, including radiotherapy and chemotherapy. The development of (Poly (ADP-ribose) Polymerase) PARP inhibitors that exploit the lack of HR also offers a therapeutic approach to glioblastoma patients with BRCA1 mutations. Despite these advances, the heterogeneity of glioblastoma and its complex tumor microenvironment make the translation of such approaches into clinical practice still challenging, and there is an "unmet need". This review discusses the current mechanisms of etiology and potential treatment of BRCA1-related glioblastoma.

Background: Gastric cancer, characterized by its high morbidity and mortality rates, exhibits low levels of RAB37. The role and molecular mechanisms of RAB37, a small GTPase, in the pathogenesis of gastric cancer are still unclear.

Methods: We assessed RAB37 expression in gastric cancer cells using quantitative Polymerase Chain Reaction (qPCR), Western blot, and immunohistochemical staining (IHC), and analyzed EMT marker proteins and autophagy changes via Western blot, immunofluorescence (IF), and transmission electron microscopy (TEM). Co-immunoprecipitation (co-IP) was used to identify protein-protein interactions. We studied the migration and invasion of gastric cancer cells using wound healing and transwell assays in vitro and a mouse pulmonary metastasis model in vivo.

Results: Overexpression of RAB37 suppressed EMT, invasion, and migration while enhancing autophagy in gastric cancer cells, which was dependent on its GTPase activity. However, all these effects could be reversed by the autophagy inhibitor chloroquine. Regarding the molecular mechanism, RAB37 strengthened the interaction between p62 and β-catenin, which consequently enhanced the p62-mediated autophagic degradation of β-catenin. Furthermore, RAB37 curbed the pulmonary metastasis of both general and cisplatin-resistant gastric cancer cells.

Conclusion: The low level of RAB37 reduces interaction between p62 and β-catenin and then the autophagic degradation of β-catenin, thereby promoting the EMT, invasion, and migration in gastric cancer cells. The low expression of RAB37 in gastric cancer suggests a potential therapeutic target, especially for cisplatin-resistant gastric cancer.

Purpose: Phosphoglycerate dehydrogenase (PHGDH), a pivotal enzyme in serine synthesis, plays a key role in the malignant progression of tumors through both its metabolic activity and moonlight functions. This study aims to elucidate the non-canonical function of PHGDH in promoting hepatocellular carcinoma (HCC) metastasis through its interaction with methyltransferase-like 3 (METTL3), potentially uncovering a novel therapeutic target.

Methods: Western blot was used to study PHGDH expression changes under anoikis and cellular functional assays were employed to assess its role in HCC metastasis. PHGDH-METTL3 interactions were explored using GST pull-down, Co-immunoprecipitation and immunofluorescence assays. Protein stability and ubiquitination assays were performed to understand PHGDH's impact on METTL3. Flow cytometry, cellular assays and nude mice model were used to confirm PHGDH's effects on anoikis resistance and HCC metastasis in vitro and in vivo.

Results: PHGDH is upregulated under anoikis conditions, thereby enhancing the metastatic potential of HCC cells. By interacting with METTL3, PHGDH prevents its ubiquitin-dependent degradation, resulting in higher METTL3 protein levels. This interaction upregulates epithelial-mesenchymal transition related genes, contributing to anoikis resistance and HCC metastasis. Nude mice model confirms that PHGDH's interaction with METTL3 is crucial for driving HCC metastasis.

Conclusion: Our research presents the first evidence that PHGDH promotes HCC metastasis by interacting with METTL3. The PHGDH-METTL3 axis may serve as a potential clinical therapeutic target, offering new insights into the multifaceted roles of PHGDH in HCC metastasis.

Ovarian cancer, a leading cause of gynecological cancer deaths globally, poses significant treatment challenges. Cisplatin (CDDP) is the first treatment choice for ovarian cancer and it is initially effective. However, 80% of ovarian cancer patients eventually relapse and develop resistance, resulting in chemotherapy failure. Therefore, finding new treatment combinations to overcome ovarian cancer resistance can provide a new tactic to improve the ovarian cancer patients' survival rate. We first identified activation of the Unfolded Protein Response (UPR) in CDDP-resistant ovarian cancer cells, implicating the IRE1α/XBP1 pathway in promoting resistance. Our findings demonstrate that inhibiting IRE1α signaling can re-sensitizes resistant cells to CDDP in vivo and in vitro, suggesting that IRE1α inhibitor used in conjunction with CDDP presumably could merge as a novel therapeutic strategy. Here, our research highlights the critical role of IRE1α signaling in mediating CDDP resistance, and paves the way for improved treatment options through combinatorial therapy.