Cancer Biology & Therapy最新文献

Abnormally expressed long non-coding (lnc)RNAs are closely associated with the pathogenesis of non-small cell lung cancer (NSCLC); thus, the present study aimed to investigate the potential role of SNHG12 in NSCLC. Transmission electron microscopy and nanoparticle tracking analysis were conducted to verify NSCLC cell-derived small extracellular vesicles (sEVs). MicroRNA (miRNA/miR) and mRNA expression levels were determined using reverse transcription-quantitative PCR, while protein expression levels were determined using western blot analysis and immunofluorescence. In addition, potential binding sites between miR-326 and SNHG12/SLC7A11 were verified using a dual-luciferase reporter assay. Cell behavior was detected using flow cytometry, colony formation, wound healing and Transwell assays, and xenograft experiments were conducted to confirm the roles of SNHG12 in NSCLC. H&E staining was used for histological analysis, and each experiment was repeated three times. Results of the present study demonstrated that NSCLC-derived SNHG12 promoted type-2 tumor-associated macrophage (TAM2) polarization. However, the decrease of SNHG12 expression in EVs reduced TAM2 polarization, weakened NSCLC cell proliferation, migration and invasion, and promoted tumor cell ferroptosis. Moreover, results of the present study revealed that SNHG12 knockdown markedly suppressed tumor growth and the metastasis of NSCLC. In addition, SNHG12 upregulated SLC7A11 expression via binding to miR-326. Overexpressed SLC7A11 promoted tumor aggressiveness and suppressed the ferroptosis of NSCLC cells. Collectively, results of the present study revealed that SNHG12 suppressed ferroptosis and promoted the metastasis of NSCLC, further demonstrating that high SNHG12 expression levels may be indicative of poor clinical outcomes for patients with NSCLC. Thus, the present study highlighted that the SNHG12/miR-326/SLC7A11 axis may exhibit potential as a novel target for the treatment of NSCLC.

Targeted therapy-induced resistance is a significant factor contributing to treatment failure in patients with gastrointestinal stromal tumors (GIST). Despite the identification of the long non-coding RNA (lncRNA) OIP5-AS1 as a critical player in human malignancy development, its role in GIST-related drug resistance remains largely unexplored. This study revealed substantial up-regulation of both OIP5-AS1 and SOX9, alongside significant down-regulation of miR-145, within sunitinib-resistant GIST cells. OIP5-AS1 emerged as a competing endogenous RNA, exerting inhibition on miR-145 while concurrently promoting the expression of SOX9. Exosome-mediated transfer of OIP5-AS1 induced heightened proliferation and invasion of GIST cells, culminating in the induction of chemoresistance to sunitinib through the miR-145/SOX9 axis. The knockdown of OIP5-AS1-expressing exosomes resulted in reduced cell proliferation and invasion in chemo-resistant GIST cells. In summary, these findings collectively suggest that OIP5-AS1 fosters GIST cell proliferation and invasion by suppressing miR-145 and up-regulating SOX9, ultimately contributing to drug resistance and tumor progression in GIST.

This study was conducted to investigate the in vitro differences in killing effects and cellular death pathways in human bronchial epithelial BEAS-2B cells, human lung adenocarcinoma A549 cells, human lung squamous carcinoma H520 cells, and human lung small cell carcinoma H446 cells mediated by hematoporphyrin derivative (HPD) at 630 nm laser wavelength. Our results showed that the viability of the BEAS-2B, A549, H520, and H446 cells gradually decreased with increasing HPD concentration after HPD-PDT. HPD-PDT induced an increase in intracellular ROS production (p < 0.05), with H520 > A549 > H446 > BEAS-2B. HPD-PDT resulted in intracellular chromatin fixation and dense nuclear staining and induced apoptosis, with apoptosis rates of H520 > A549 > H446 > BEAS-2B. The western blotting (WB) results showed that HPD-PDT could lead to reduced BCL-2 protein levels, upregulate BAX protein expression and activate caspase-3 protein, and induce autophagy, as evidenced by the increased expression of the autophagy-related proteins ATG5, Beclin-1 and LC3B in all cells tested. However, apoptosis-inducing proteins and autophagy proteins were statistically different in these four cell types. Our study confirms that HPD-mediated phototoxicity varied in the different cell lines, indicating that lung cancer cells die due to the interactions of different cell death pathways rather than the same well-defined mechanisms.

Bladder cancer (BC) remains challenging due to its recurrence and metastasis, with METTL3-mediated m⁶ A RNA modification emerging as a key oncogenic driver. This review synthesizes METTL3's roles in BC progression, including tumor initiation, metastasis, stemness, and therapy resistance. We detail its regulation of critical pathways (e.g. HIF1A/IGF2BP3/BIRC5, AFF4/NF-κB/c-MYC) and dual functions in RNA stability and epigenetic crosstalk with DNA methylation. METTL3 promotes chemoresistance (e.g. circ0008399/WTAP/TNFAIP3) and immune evasion (PD-L1 stabilization), while its overexpression correlates with poor prognosis and cisplatin resistance. By integrating METTL3's interactions with m⁶ A readers (YTHDF1/2, IGF2BP3) and erasers (ALKBH5), we propose targeting METTL3 as a strategy to enhance chemotherapy and immunotherapy efficacy. This work underscores METTL3's potential as a diagnostic biomarker and therapeutic target, advancing precision oncology in BC.

Trial registration: Trial no. NCT04821778 registered in ClinicalTrials.gov.

Adipose-derived exosomes (ADEs), a subtype of extracellular vesicles, are critical mediators of communication between adipose tissue and tumors, playing pivotal roles in cancer progression and therapeutic response. These nanoscale vesicles carry microRNAs, proteins, and lipids that influence tumor cell proliferation, migration, metastasis, and immune modulation. The dual functions of ADEs - both in promoting and suppressing tumorigenesis - are largely dependent on their cellular origin, molecular cargo, and the characteristics of the tumor microenvironment. Recent studies have identified ADEs as potential diagnostic biomarkers, therapeutic targets, and drug delivery platforms, offering promising avenues for precision oncology. However, significant challenges - such as biological heterogeneity, lack of standardization in production, concerns regarding efficacy and safety, and regulatory constraints - continue to hinder their clinical translation. This review aimed to explore the multifaceted roles of ADEs in cancer pathogenesis, their therapeutic potential, and current limitations, providing insights to guide future research and clinical applications.

Lenvatinib, as a multi-kinase inhibitor, has been approved as a first-line drug for patients with advanced hepatocellular carcinoma (HCC). Gasdermin E (GSDME)-mediated pyroptosis, a form of programmed cell death, can be induced by chemotherapy drugs or certain kinase inhibitors. However, the role of Lenvatinib in inducing pyroptosis in HCC warrants further investigation. Phase contrast microscopy, LDH assays, and gain- and loss-of-function strategies were used to evaluate Lenvatinib-induced pyroptosis in HCC cells. GSDME palmitoylation was assessed via the acyl-biotin exchange method. In vivo, a subcutaneous HCC xenograft model in nude mice were established to assess the effects of interfering with GSDME on the sensitivity of HCC to Lenvatinib. Lenvatinib induced pyroptosis in HCC cells in a dose- and time-dependent manner. Additionally, Lenvatinib promoted GSDME cleavage, with upregulation of GSDME enhancing pyroptosis and downregulation reducing this effect. The ABE method revealed that GSDME is palmitoylated, and Lenvatinib increased its palmitoylation, promoting plasma membrane localization and enhancing protein stability. Inhibition of GSDME palmitoylation by 2-BP blocked Lenvatinib-induced pyroptosis. In vivo, upregulation of GSDME increased HCC sensitivity to Lenvatinib and inhibited tumor growth. Lenvatinib induces pyroptosis in HCC by promoting the palmitoylation of GSDME, enhancing its localization to the plasma membrane and increasing its protein stability. Interfering with GSDME, both in vitro and in vivo, affects Lenvatinib-induced pyroptosis, thereby altering the therapeutic sensitivity of HCC to Lenvatinib. Targeting GSDME palmitoylation represents a potential therapeutic strategy for HCC, as it enhances Lenvatinib-induced pyroptosis and improves the therapeutic response.

Background and purpose: Bone metastasis is common for breast cancer and associated with poor prognosis. Currently, radiotherapy (RT) serves as the standard treatment for patients exhibiting symptoms of bone metastasis to alleviate pain. Whether earlier application of RT will better control bone metastasis remains unclear.

Methods: We utilized a mouse model of breast cancer bone metastasis by intra-femoral injection of 4T1-luc breast tumor cells. The bone metastasis was treated by RT using various doses, timings, and modalities. Tumor growth was assessed through bioluminescence imaging, and lung metastases was quantified following lung tissue fixation. Flow cytometry was employed to analyze alterations in immune cell populations.

Results: Single high-dose RT suppressed tumor growth of bone metastases, but caused severe side effects. Conversely, fractionated RT mitigated tumor growth in bone metastases with fewer adverse effects. Fractioned RT initiated at the early stage of bone metastasis effectively inhibited tumor growth in the bone, suppressed secondary lung metastases, and prolonged mouse survival. In line with the known pro- and anti-metastatic effects of neutrophils and T cells in breast cancer, respectively, earlier fractioned RT consistently decreased the proportions of neutrophils while increased the proportions of T cells in both the bone and the lung tissues.

Conclusion: The data suggest that fractionated RT can inhibit the progression of early stage of bone metastasis and reduce secondary lung metastasis, leading to favorable outcomes. Therefore, these findings provide preclinical evidence to support the application of fractionated RT to treat patients with bone metastasis as earlier as possible.

Breast cancer remains a global health challenge with varied prognoses despite treatment advancements. Therefore, this study explores the pseudogene MGAT4EP as a potential biomarker and therapeutic target in breast cancer. Using TCGA data and bioinformatics, MGAT4EP was identified as significantly overexpressed in breast cancer tissues and associated with poor prognosis. Multivariate Cox regression confirmed MGAT4EP as important prognostic factor. A clinical prediction model based on MGAT4EP expression showed high accuracy for 1-, 3-, and 5-year survival rates and was translated into a nomogram for clinical application. Functional studies revealed that silencing MGAT4EP via siRNA promoted apoptosis, inhibited migration and invasion in breast cancer cells. RNA-seq, GSEA, and GO analyses linked MGAT4EP to apoptosis and focal adhesion pathways. Notably, knock down of MGAT4EP significantly suppressed tumor growth and metastasis in xenograft and lung metastasis models. Taken together, these findings establish MGAT4EP as an attractive target for metastatic breast cancer and provide a potential a promising therapeutic target for breast cancer treatment.

Increased levels of intratumoral free iron drive more aggressive behavior with the development of treatment resistance and spread in a range of cancers including prostate cancer (PCa). This phenotype is associated with an increase in TFRC expression and a decrease in FTH1, a profile supporting increased iron acquisition. In this study we investigated the anti-oncogenic effects of two small peptides (FT-002 and FT-005) that upregulate FTH1 expression and downregulate TFRC expression when combined with standard androgen receptor pathway inhibitors (ARPIs) in xenograft models of PCa in male athymic nude mice. The PC3 cell line was used to establish xenografts representing highly aggressive, androgen-resistant PCa and the LNCaP cell line as a model of androgen-sensitive PCa. Both peptides enhanced the anti-tumor efficacy of ARPI therapy. Efficacy was more marked with the combination of the second-generation APRI enzalutamide than the first-generation agent bicalutamide, a result consistent with known resistance mechanisms to different ARPI therapy. Further, the FT-peptide/enzalutamide combination drove tumor regression whereas enzalutamide monotherapy only slowed growth, even in the hormone-sensitive xenograft. The FT-002a-enzalutamide combination was more effective than FT-005 in reducing tumor mass and volume and modulating FTH1 and TFRC expression. The reversal by the peptides of this oncogenic expression pattern points to a reduction in the tumor free iron via increased iron storage in ferritin and a reduction in iron influx via the transferrin receptor. Peptide-mediated modulation of tumor iron metabolism may therefore offer a novel means to enhance ARPI efficacy and delay resistance in advanced prostate cancer.