Cancer Biology & Therapy最新文献

Lung cancer is the most common cancer worldwide. The stemness and metastasis of tumor cells present major challenges to effective lung cancer treatment. Beta-hydroxybutyrate (BHB), a ketone body, plays a key role in various cancers. However, whether BHB mediates the progression of non-small cell lung cancer (NSCLC) remains unclear. The effects of BHB on the proliferation, apoptosis, and metastasis of NSCLC cells were assessed using the Cell Counting Kit 8, flow cytometry, western blotting, and Transwell assays. The sphere formation assay was used to evaluate the impact of BHB on NSCLC cell stemness. The underlying molecular mechanism was investigated through knockdown and overexpression of free fatty acid receptor 3 (FFAR3) using shRNAs and expression vectors in two NSCLC cell lines (NCI-H1975 and PC-9). In vivo, xenograft tumor and liver metastasis models were established in nude mice. BHB treatment reduced viability, stemness, and migratory and invasive abilities of NSCLC cells. BHB also induced apoptosis and increased cleaved caspase-3 levels in these cells. Moreover, BHB suppressed tumor growth and metastasis, and reduced cell stemness in NSCLC tissues in vivo. Mechanistically, FFAR3 knockdown abolished, while FFAR3 overexpression enhanced, the tumor-suppressive effects of BHB, identifying FFAR3 as a key mediator. These data shed light on the role of BHB in NSCLC development and its underlying molecular mechanisms, suggesting a promising treatment strategy for patients with NSCLC.

Triple negative breast cancer (TNBC), a highly invasive breast cancer, is one of the leading causes of cancer-related mortality worldwide. Although chemotherapy remains the standard of care for TNBC, the development of chemotherapy resistance significantly limits its clinical efficacy. In this study, we identified the deubiquitinating enzyme USP44 as a contributor to chemoresistance in TNBC and investigated the potential regulatory feedback mechanisms involved. In this experimental study, we investigated the sensitivity of TNBC cells MDA-MB-231 and BT-549 to chemotherapy drugs after overexpression and knockdown of USP44 using CCK-8 reagent kit and flow cytometry analysis, respectively. Western blot was performed to evaluate the expression levels of relevant proteins. In vivo xenograft models were established to examine the effects of USP44 and its downstream targets on chemosensitivity. Co-immunoprecipitation assay and ubiquitination assay were conducted to identify interacting proteins and elucidate the underlying molecular mechanisms. Knockdown of USP44 increased the sensitivity of MDA-MB-231 and BT-549 cells to chemotherapeutic agents, accompanied by elevated levels of Cleaved PARP. In contrast, USP44 overexpression reduced drug sensitivity. Mechanistically, USP44 was found to interact with EZH2, preventing its ubiquitination and subsequent proteasomal degradation. Notably, treatment with GSK126, a specific EZH2 inhibitor, reversed the chemoresistance induced by USP44 overexpression. USP44/EZH2 signaling pathway is one of the key to causing the drug resistance of TNBC, warranting further clinical investigation.

Early and precise diagnosis of cancer is pivotal for effective therapeutic intervention. Traditional diagnostic methods, despite their reliability, often face limitations such as invasiveness, high costs, labor-intensive procedures, extended processing times, and reduced sensitivity for early-stage detection. Electrochemical biosensing is a revolutionary method that provides rapid, cost-effective, and highly sensitive detection of cancer biomarkers. This review discusses the use of electrochemical detection in biosensors to provide real-time insights into disease-specific molecular interactions, focusing on target recognition and signal generation mechanisms. Furthermore, the superior efficacy of electrochemical biosensors compared to conventional techniques is explored, particularly in their ability to detect cancer biomarkers with enhanced specificity and sensitivity. Advancements in electrode materials and nanostructured designs, integrating nanotechnology, microfluidics, and artificial intelligence, have the potential to overcome biological interferences and scale for clinical use. Research and innovation in oncology diagnostics hold potential for personalized medicine, despite challenges in commercial viability and real-world application.

Dysfunction or dysregulation of deubiquitination is closely related to the initiation and development of multiple cancers. Targeted regulation of deubiquitination has been recognized as an important strategy in tumor therapy. However, the mechanism by which drugs regulate deubiquitinase is not clear. Here, we identified ubiquitin-specific peptidase 48 (USP48), a member of the ubiquitin-specific protease family highly expressed in various tumors, as a specific substrate for the activated caspase-3. During drug induced apoptosis of AML cells, activated caspase-3 cleaves USP48 through recognizing the conservative motif DEQD located at 611-614 sites of human USP48. Subsequent analysis showed that the cleavage USP48 N-terminal fragment which contains catalytic active domain is easily degraded by ubiquitination. Meanwhile knockdown experiment showed that inhibiting the expression of USP48 could also promotes apoptosis and enhance the efficacy of chemotherapy drugs. Altogether, these results suggest that targeting USP48 may represent a novel therapeutic strategy in AML.

Ectopic hepatocellular carcinoma (EHCC) demonstrates morphological and immunohistochemical features identical to conventional intrahepatic hepatocellular carcinoma (HCC), originating from ectopic liver tissue (EL), which is defined as a hepatic organ or tissue not connected to the mother liver. EHCC is a rare disease and difficult to diagnose preoperatively. Therefore, its epidemiology, treatment, and prognosis are not fully elucidated. Herein, we present a case report of a 52-year-old male diagnosed with unresectable EHCC who underwent transarterial chemoembolization (TACE) and succumbed to the disease 13 months after treatment, accompanied by a literature review summarizing the epidemiology while analyzing therapeutic strategies and prognostic outcomes in EHCC through synthesis of published case evidence.

Triple-negative breast cancer (TNBC) is a common malignant disease among females and severely threatens the health of women worldwide. Nowadays, circular RNAs (circRNAs) aroused our interest for their functions in human cancers, including TNBC. However, the mechanism of most circRNAs in the progression of TNBC remains unclear. We found a novel circRNA named circATP5C1, whose function in TNBC remains uncovered. Tissue microarray was used to analyze the association between the expression of circATP5C1 and the prognoses of TNBC patients. Gain-and loss-of-function experiments were performed to validate the biological functions of circATP5C1 in different TNBC cell lines. RNA-seq analyses were conducted to find out the target genes regulated by circATP5C1. RNA pull-down assay and mass spectrometry were used to select the proteins associated with circATP5C1. RNA FISH-immunofluorescence and RNA immunoprecipitation (RIP) were complemented to validate the interaction between circATP5C1 and its binding protein. CircATP5C1 was identified to have predictive function in prognosis of TNBC patients. CircATP5C1 advanced the progression of TNBC cells. Mechanistically, Colony stimulating factor 1 (CSF-1) is a vital downstream gene regulated by circATP5C1. The alteration of CSF-1 expression level was validated due to the interaction between circATP5C1 and insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2). Rescue experiments demonstrated that circATP5C1 accelerates the progression of TNBC partly via binding with IGF2BP2 to increase the secretion of CSF-1. This study uncovers a novel mechanism of circATP5C1/IGF2BP2/CSF-1 pathway in regulating progression of TNBC.

Hypoxia-induced Pyrroline-5-Carboxylate Reductase 1 (PYCR1) is implicated in bladder cancer (BC), but its specific role remains elusive. This study investigated how PYCR1 promotes BC progression through glycolysis, histone H3 Lysine 18 Lactylation (H3K18la), and Solute Carrier Family 6 Member 14 (SLC6A14)-driven glutamine catabolism. Here, BC cell lines were cultured under hypoxia to evaluate changes in PYCR1 expression, glycolysis, and lactate production. The xenograft and metastasis models in nude mice were used to validate the role of the PYCR1/H3K18la/SLC6A14 axis in BC progression. GEPIA Bioinformatics database data showed that PYCR1 was upregulated in BC and was associated with poor prognosis. The PYCR1 positive expression rate in BC tissues was increased. Hypoxia induced PYCR1 expression in BC cells, enhancing glycolysis and lactate production, which increased H3K18la levels. Upregulated SLC6A14 expression promoted glutamine catabolism and enhanced BC cell proliferation, migration, and invasion. PYCR1 knockdown inhibited H3K18la levels, SLC6A14 expression, and BC cell aggressiveness; SLC6A14 overexpression reversed these effects. In vivo experiments confirmed that the PYCR1/H3K18la/SLC6A14 axis is critical for hypoxia-driven BC growth and metastasis. In summary, Hypoxia-induced PYCR1 enhances glycolysis, leading to increased lactate production and elevated H3K18la levels, which upregulates SLC6A14 transcription and glutamine catabolism, thereby promoting BC growth and metastasis.

Cisplatin (DDP) resistance is a key factor hindering esophageal cancer (ESCA) treatment. Exosomes have been reported to confer resistance to DDP in various tumor cells. However, the effects of ESCA cell-derived exosomes and exosomal human antigen R (HuR) on DDP resistance in cancer cells have not been elucidated. In this study, isolated exosomes were identified by transmission electron microscopy, nanoparticle tracking analysis, and western blotting. CCK-8 and flow cytometry were employed to assess the functional role of exosomes in ESCA DDP-resistant cells and their parental cells. Bioinformatics analysis was performed to identify molecules that were positively associated with HuR and validated using dual-luciferase reporter analysis and RNA immunoprecipitation assays. We found that exosomes from ESCA cells enhance the resistance of drug-resistant cells to DDP. Importantly, HuR protein, but not mRNA, was directly transferred into DDP-resistant cells via exosomes, thereby increasing the level of HuR protein. Mechanistically, HuR positively correlated with Lamin B2 (LMNB2) in ESCA cells, and ESCA DDP-resistant cells transfected with siRNA targeting LMNB2 exhibited reduced cell viability and elevated apoptosis rates. Moreover, the role of ESCA cell-derived exosomes in the transmission of DDP resistance in vivo was validated using a nude mouse model. Collectively, our results revealed that exosomes exposed to ESCA cells induced greater drug resistance in DDP-resistant ESCA cells via HuR delivery. Targeting HuR or its positively related target LMNB2 may present new therapeutic opportunities for treating patients with DDP-resistant ESCA.

Pancreatic ductal adenocarcinoma (PDAC) poses a significant challenge in oncology due to its dismal prognosis and limited therapeutic options. In this study, we investigated the role of miR-301a in facilitating crosstalk between the Hedgehog (Hh) and HIPPO/YAP signaling pathways during the progression of PDAC. Our findings revealed that miR-301a served as a central regulatory node, targeting Gli1 within the Hh pathway and STK4 within the HIPPO/YAP pathway. Immunohistochemical and molecular analyses confirmed dysregulation of pathway components in pancreatic cancer, underscoring the pivotal role of miR-301a. Functional assays demonstrated the impact of miR-301a on cell proliferation and apoptosis, particularly in synergy with TNF-α. Overall, our study elucidated the intricate interplay between the Hh and HIPPO/YAP pathways mediated by miR-301a, providing valuable insights into potential therapeutic strategies for intervening in PDAC.

Nearly 20 million people are diagnosed with cancer each year with breast cancer being the most common among women. Triple negative breast cancer (TNBC), defined by its no/low expression of ER and PR and lack of amplification of HER2, makes up 15-20% of all breast cancer cases. While patients overall have a higher response to chemotherapy, this subgroup is associated with the lowest survival rate indicating significant clinical and molecular heterogeneity demanding alternate treatment options. Therefore, new therapies have been explored, with a large focus on utilizing the immune system. A whole host of immunotherapies have been studied including immune checkpoint inhibitors, now standard of care for eligible patients, and possibly the most exciting and promising is that of a TNBC vaccine. While currently there are no approved TNBC vaccines, this review highlights many promising studies and points to an antigen, p53, which we believe is highly relevant for TNBC.