Cancer Biology & Therapy最新文献

Introduction: Lung adenocarcinoma (LUAD) is one of the leading causes of cancer-related deaths worldwide. While NCAPD2 has been implicated in promoting tumorigenesis across various cancer types, its specific role in LUAD remains underexplored. This study aims to elucidate the molecular mechanisms by which NCAPD2 contributes to LUAD progression, with a focus on its involvement in the AKTMDM2/E2F1 positive feedback loop.

Materials and methods: NCAPD2 expression in LUAD and normal tissues was analyzed using Western blotting and immunohistochemistry (IHC). Functional assays, including colony formation, wound healing, Transwell assays, and in vivo mouse models were conducted to evaluate the impact of NCAPD2 on LUAD cell proliferation, invasion, and metastasis. RNA sequencing and protein interaction experiments were used to investigate the role of NCAPD2 in the PI3K/AKT/MDM2 pathway and its interaction with E2F1.

Results: This study first identified that NCAPD2 expression is significantly upregulated in LUAD tissues, particularly in higher pathological stages. NCAPD2 overexpression promoted LUAD cell proliferation and metastasis, while its knockdown inhibited tumor growth and invasion. Mechanistically, NCAPD2 activated the PI3K/Akt pathway, facilitating the interaction between MDM2 and E2F1, reducing E2F1 ubiquitination, and increasing its expression. Furthermore, E2F1 enhanced NCAPD2 transcription, forming a positive feedback loop that drives LUAD progression.

Conclusion: This study reveals a novel role of NCAPD2 in promoting LUAD progression through the AKT/MDM2/E2F1 positive feedback loop. These findings provide new insights into the molecular pathogenesis of LUAD and suggest NCAPD2 as a potential therapeutic target for improving patient outcomes.

Ovarian cancer is one of the most malignant tumors in women. Long noncoding RNAs have been demonstrated to regulate multiple biological processes, including cell proliferation, migration, apoptosis, and drug resistance, in various cancers. Small nucleolar RNA (snoRNA) host genes (SNHGs) are a group of long noncoding RNAs. Studies have reported that SNHGs are aberrantly expressed in many kinds of cancers and are associated with poor patient prognosis. In ovarian cancer, SNHGs play critical roles in the development and progression of ovarian cancer via different pathways. However, there is a lack of systematic reports on the research progress of SNHGs in ovarian cancer. Therefore, we reviewed the studies on the roles of SNHGs in the early diagnosis, development, and treatment of ovarian cancer and explored the underlying mechanisms to provide new insights into the treatment of ovarian cancer.

Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality due to delayed diagnosis and poor prognosis. Long non-coding RNAs (lncRNAs) are key cancer regulators, yet the role of C1orf21-DT (PIG13-DT) in HCC remains unclear.

Methods: We evaluated PIG13-DT expression in HCC and paired adjacent non-tumorous tissues. Functional studies were conducted using cell culture, cell-derived xenotransplantation (CDX) models, and molecular techniques including RNA pull-down, mass spectrometry, RIP-qPCR, and RNA sequencing. We explored the interplay between PIG13-DT, RNA-binding protein YBX3, and USP15 mRNA.

Results: PIG13-DT was highly expressed in HCC tissues compared with normal tissues and associated with poor prognosis. Functionally, PIG13-DT enhanced cancer stem cell (CSC) function, reduced reactive oxygen species (ROS) levels, and promoted HCC cell proliferation and migration. Mechanistically, PIG13-DT interacted with YBX3, stabilizing YBX3 and promoting USP15 mRNA translation and stability, thus driving HCC progression. Clinical data from lenvatinib-treated HCC patients showed that PIG13-DT expression was correlated with poor treatment response.

Conclusion: Our study identifies a novel PIG13-DT/YBX3/USP15 axis driving HCC progression, suggesting PIG13-DT as a potential biomarker and therapeutic target. This work provides new insights into HCC molecular mechanisms and offers potential diagnostic and therapeutic implications.

Mesothelin (MSLN) is a glycosylphosphatidylinositol (GPI)-anchored membrane protein that promotes malignant behaviors including tumor cell proliferation, migration and immune evasion through activation of multiple signaling pathways, such as MAPK/ERK and PI3K/AKT. MSLN is widely overexpressed in malignant tumors but shows low expression levels in normal tissues. This differential expression pattern renders MSLN an important clinical therapeutic target. Currently, MSLN-based tumor-targeting approaches predominantly involve antibody-drug conjugates (ADC), cancer vaccines, oncolytic viruses and chimeric antigen receptor T-cell (CAR-T) therapies. These therapeutic modalities have demonstrated encouraging efficacy in preclinical studies and phase I/II clinical trials. However, challenges such as unclear molecular mechanisms of MSLN signaling pathways and extracellular domain shedding impose limitations on targeted therapeutic strategies. Therefore, this review comprehensively discusses the gene and protein structures of MSLN, its biological functions, and related targeted therapeutic strategies, providing new insights into MSLN-targeted cancer therapy.

Background: Triple-negative breast cancer (TNBC) is an aggressive subtype with a poor prognosis and limited treatment options. Tumor-associated macrophages (TAMs), the predominant and abundant immune cells in the tumor immune microenvironment (TIME), critically drive TNBC progression. Consequently, TAM reprogramming has emerged as a promising therapeutic approach. However, a major barrier remains the incomplete understanding of the molecular mechanisms governing TAM reprogramming.

Methods: The role of CD44v5 in TAM polarization was evaluated with a CD44v5 monoclonal antibody and CD44v5-knockdown cell lines. Subsequently, cell functional assays, including wound healing, invasion, and colony formation assays, were performed to assess changes in the MDA-MB-468 cell line. Cytokine secretion levels (IL-4 and IL-6) were measured by electrochemiluminescence immunoassay (ECLIA).

Results: We found that M2 macrophages and tumor-associated macrophages (TAMs) polarized through the IL4/IL4R signaling pathway and exerted similar protumorigenic functions, and that IL4 is the key protumorigenic factor secreted by M2 macrophages. Interestingly, CD44v5 blockade effectively inhibited M2 polarization and promoted the phenotypic shift to M1 macrophages, which was supported by increased CD86 expression and decreased IL-4 secretion. Furthermore, molecular docking analysis and colocalization microscopy confirmed that CD44v5 colocalized with IL-4Rα, preventing its internalization.

Conclusion: CD44v5 promotes M2 macrophage polarization by stabilizing and enhancing the IL-4Rα/STAT6/IL-4 signaling pathway, thereby facilitating the progression of triple-negative breast cancer. CD44v5 serves as an important therapeutic target for the reprogramming of both TAMs and M2 macrophages, thereby providing a novel strategy for the treatment of TNBC.

Background: Natural killer/T-cell lymphoma (NKTCL) presents highly aggressive clinical behaviour, and the outcomes for relapsed and refractory patients are still poor. Our previous study identified somatic mutations in GNAQ in 8.7% of cases through whole-exome sequencing, revealing the T96S mutation in the Gαq protein.

Materials: The proliferation, gemcitabine sensitivity and apoptosis of NKTCL cells were assessed by CCK-8 assays and flow cytometry. The downstream pathways of GNAQ were explored by mRNA sequencing, Western blotting and co‑immunoprecipitation. Additionally, we investigated the role of GNAQ in the activation of the RHOA pathway in NKTCL.

Results: We found that GNAQ significantly inhibited the aggressive function of NKTCL, whereas the T96S mutation abolished the ability of wild-type GNAQ to trigger cell apoptosis. Further investigation revealed that GNAQ modulated NKTCL cell functions through the activation of the RHOA pathway, which is regulated by the GNAQ-ARHGEF25 complex. Clinically, high expression of RHOA was associated with improved overall survival (HR = 0.317, 95% CI: 0.126-0.800, p = 0.015), whereas low expression of RHOA was correlated with poorer survival outcomes. The application of an RHOA pathway inhibitor or reactivation of the RHOA pathway significantly affected the biological functions of NKTCL cells both in vitro and in vivo.

Conclusion: In summary, RHOA is a critical downstream effector of GNAQ in NKTCL. GNAQ promotes RHOA activation through ARHGEF25, which in turn regulates cellular functions by modulating cell proliferation and apoptosis, thereby influencing the progression of NKTCL.

Lactylation, a recently identified post-translational modification, has reshaped our understanding of lactate from a metabolic byproduct to a central regulator of tumor biology. Accumulating evidence reveals that lactate-driven lactylation orchestrates metabolic reprogramming, epigenetic remodeling, immune evasion, metastasis, and therapeutic resistance, thereby fueling malignant progression. Beyond histones, diverse non-histone substrates further expand its regulatory network across cancer signaling pathways. We highlight the crosstalk between lactylation and other modifications, its role in tumor heterogeneity, and the therapeutic opportunities arising from targeting this pathway. These insights establish lactylation as both a hallmark and a potential vulnerability of cancer, opening new avenues for precision oncology.

Background: Clear cell renal cell carcinoma (ccRCC), the most common kidney cancer subtype, is marked by lipid metabolism reprogramming and therapy resistance. Ferroptosis-an iron-dependent, lipid peroxidation-driven cell death-has gained attention as a therapeutic strategy. This study investigates the role of ACSL1, a key lipid metabolism enzyme, in ccRCC.

Methods: Using TCGA/GEO datasets, qPCR, immunohistochemistry, and immunofluorescence, ACSL1 expression and clinical significance were analyzed. Functional assays with ACSL1-overexpressing ccRCC cells and a xenograft mouse model evaluated its impact on tumor behavior. Transcriptomics and lipidomics, alongside ROS, ferroptosis, and p53 inhibitors, were applied to uncover mechanisms.

Results: ACSL1 is markedly downregulated in ccRCC and predicts poor prognosis. Overexpression suppressed proliferation and migration, induced cell death, and slowed tumor growth. Mechanistically, ACSL1 elevated ROS, activated p53, downregulated SLC7A11/GPX4, and triggered ferroptosis. Blocking ROS or p53 reversed these effects, confirming a ROS-p53-SLC7A11/GPX4 feedback loop.

Conclusion: ACSL1 functions as a tumor suppressor in ccRCC by inducing ferroptosis via the ROS-p53-SLC7A11/GPX4 axis. It holds promise as a prognostic biomarker and therapeutic target in ccRCC.

Background: Double-hit lymphoma (DHL) exhibits aggressive behavior due to dysregulated proliferation and resistance to apoptosis. Current therapies, including R-CHOP, show limited efficacy, necessitating novel strategies. 9-ING-41, a novel ATP-competitive small-molecule inhibitor that targets glycogen synthase kinase-3β (GSK-3β), has emerged as a promising therapeutic agent because of its ability to disrupt oncogenic signaling pathways associated with tumor progression and treatment resistance. However, the antitumor effects of 9-ING-41 in DHL remain unclear.

Materials and methods: DHL cell lines (Karpas-422 and SuDHL2) were treated with venetoclax and 9-ING-41, either alone or in combination. Cell viability in cytotoxicity assays was assessed using the CCK-8 assay, while apoptosis and cell cycle changes were analyzed via flow cytometry. Western blotting was employed to evaluate alterations in the levels of GSK-3β and WNT/β-catenin pathway proteins following treatment.

Results: In preclinical studies utilizing DHL cell models, the single agent 9-ING-41 demonstrated robust biological activity through inducing significant G1/S phase cell cycle arrest and triggering apoptosis. When coadministered with venetoclax, a clinically approved BCL-2 inhibitor, the combination exhibited marked synergistic cytotoxicity in DHL cells, achieving superior inhibitory effects compared to either agent alone. The combined treatment enhanced cell cycle arrest, significantly reducing the number of S-phase cells and reinforcing G0/G1 arrest. Further mechanistic studies revealed that the combination modulated key proteins in the GSK-3 pathway and downstream WNT/β-catenin pathway, revealing a potential synergistic mechanism.

Conclusion: The demonstrated single-agent efficacy and combination synergy with venetoclax support the potential of 9-ING-41 as a novel therapeutic strategy for DHL. These findings provide a proof-of-concept that may serve as a basis for future preclinical investigations in DHL.

Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. Although radiotherapy (RT) is used to treat over half of NSCLC patients, about 30% have inherent or acquired radioresistance leading to treatment failure. There's a clinically unmet need to investigate mechanisms of radioresistance that can be targeted in combination with RT. Among these, HMGB1 has been shown to play a key role in tumor progression. Our research investigates TLR4, a receptor for HMGB1, highly expressed in NSCLC tissues, as a mediator of radioresistance.

Methods: The TLR4 inhibitor, TAK242, was tested in NSCLC cell lines (murine: LLCI, KLN205; human: H1975, SW900). Cells were irradiated at 2 and 10 Gy. In vivo, KLN205 cells were implanted in DBA/2 mice and tumors were irradiated at 10Gy. Gene and protein expression of TLR4 and MyD88 were assessed in vitro and in vivo. HMGB1 secretion was quantified after RT. Clonogenic assays were performed to evaluate the effect of TAK242 on radiosensitivity in vitro. The combination of TAK242 and RT was investigated in vivo in mice bearing KLN205 tumors.

Results: TAK242 significantly decreased NSCLC cell proliferation and migration. Radiation at 2 and 10 Gy increased TLR4 gene expression in vitro and in vivo in a dose-dependent manner. In vitro, TLR4 and HMGB1 protein expression was upregulated following radiation. TAK242 in combination with radiation enhanced radiosensitivity in vitro. TAK242 decreased the percentage of cells in the G1 phase, coupled with an increase in late S and G2/M, suggesting radiosensitization via cell cycle modulation. In vivo, the combination of RT and TAK242 significantly reduced growth of KLN205 tumors.

Conclusion: These findings show that TLR4 inhibition enhances RT sensitivity in NSCLC.