Cancer Biology & Therapy最新文献

The epidemic of obesity is a growing concern and is one of the major risk factors for several chronic diseases, including several types of cancers. The correlation of breast cancer with obesity has been extensively studied and involves an interplay of hormonal, metabolic, and genetic factors explored in this review. Inflammation and hormone dysregulation play an important role in promoting a protumorigenic environment through adipose tissue, which is involved in energy storage and functions as an endocrine organ. As a result, various cytokines, primarily proinflammatory in nature, are released, resulting in low-grade inflammation promoting tumor growth. Additionally, obese conditions also induce imbalances in hormones, particularly estrogen and insulin, both of which drive carcinogenesis. Genetic components such as single nucleotide polymorphisms also play critical roles in modulating the correlation between obesity and breast cancer. This review provides a comprehensive overview of various mechanisms underlying obesity and breast cancer incidence and progression.

Ribosomal S6 protein kinase 4 (RSK4), a member of the serine‒threonine kinase family, plays a vital role in the Ras‒MAPK pathway. This kinase is responsible for managing several cellular activities, including cell growth, proliferation, survival, and mobility. In this study, we observed higher RSK4 protein expression in clear cell renal cell carcinoma (ccRCC) than in normal kidney tissue, and the overexpression of RSK4 might predict poor outcomes for ccRCC patients. Notably, renal cell carcinoma (RCC) is rich in blood vessels; therefore, this study aimed to explore the biological function of RSK4 in ccRCC progression and its specific regulatory mechanism. We analyzed changes in the expression of target genes through transcriptomic and proteomic assessments. We also conducted tube formation assays and VEGF ELISAs to understand the role of RSK4 in angiogenesis. Additionally, we evaluated the regulatory effect of RUNX1 on EPHA2 transcription using a luciferase reporter gene assay and observed that the effect of RUNX1 on activating EPHA2 transcription was negated after the binding site was mutated. Our findings suggested that RSK4 enhanced tube formation by stimulating VEGF secretion. Concurrently, in vivo experiments confirmed that RSK4 expedited RCC metastasis and angiogenesis. This evidence indicates that RSK4 may serve as a new prognostic marker and play a vital role in RCC metastasis.

Metastasis is the predominant culprit of cancer-associated mortality in non-small cell lung cancer (NSCLC). Tweety homolog 3 (TTYH3) reportedly functions vitally in the development of diverse cancers, including NSCLC; nevertheless, its role in NSCLC metastasis remains ambiguous. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot were initially employed to detect TTYH3 expression in NSCLC and normal lung epithelial cells. Subsequently, A549 and NCI-H1650 cells were chosen as NSCLC models in vitro and transfected with short hairpin RNAs (sh-TTYH3, sh-LUCAT1, and sh-ALYREF) or overexpression plasmids (oe-ALYREF and oe-TTYH3). Transwell assays were used for migrative and invasive tests. Epithelial mesenchymal transformation (EMT)-related proteins (E-cadherin, N-cadherin, Vimentin, and Snail) were measured by western blot. A mouse lung metastasis model was built to define the function of TTYH3 in NSCLC metastasis, followed by hematoxylin-eosin staining. RNA pull-down, RNA immunoprecipitation, qRT-PCR, western blot, and actinomycin D assays were adopted to determine the relationships among LUCAT1, ALYREF, and TTYH3. TTYH3 was highly expressed in NSCLC cells relative to normal lung cells. Functionally, TTYH3 knockdown restrained NSCLC migration, invasion, EMT, and metastasis. Mechanistic experiments demonstrated that LUCAT1 bound to ALYREF. After LUCAT1 knockdown, TTYH3 expression and mRNA stability were reduced, which was reversed by ALYREF overexpression. Furthermore, ALYREF overexpression counteracted the inhibitory effects of LUCAT1 knockdown on NSCLC cell migration, invasion, and EMT. TTYH3 overexpression eliminated the suppressive functions of ALYREF downregulation in NSCLC progression. LUCAT1 promotes TTYH3 expression via interacting with ALYREF, thereby facilitating NSCLC migration, invasion, and EMT.

Objectives: Acute T-cell lymphoblastic leukemia (T-ALL) is a severe hematologic malignancy with limited treatment options and poor long-term survival. This study explores the role of IKZF1 in regulating BCL-2 expression in T-ALL.

Methods: CUT&Tag and CUT&Run assays were employed to assess IKZF1 binding to the BCL-2 promoter. IKZF1 overexpression and knockdown experiments were performed in T-ALL cell lines. The effects of CX-4945 and venetoclax, alone and in combination, were evaluated in vitro and in vivo T-ALL models.

Results: CUT&Tag sequencing identified IKZF1 binding to the BCL-2 promoter, establishing it as a transcriptional repressor. Functional assays demonstrated that IKZF1 overexpression reduced BCL-2 mRNA levels and increased repressive histone marks at the BCL-2 promoter, while IKZF1 knockdown led to elevated BCL-2 expression. CX-4945, a CK2 inhibitor, could reduced BCL-2 levels in T-ALL cells. Notably, knockdown of IKZF1 partially rescued the CX-4945-induced repression of BCL-2. These results underscore the CK2-IKZF1 signaling axis as a key regulator of BCL-2 expression. In vitro, CX-4945 enhanced the cytotoxicity of venetoclax, with the combination showing significant synergistic effects and increased apoptosis in T-ALL cell lines. In vivo studies with cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models demonstrated that CX-4945 and venetoclax combined therapy provided superior therapeutic efficacy, reducing tumor burden and prolonging survival compared to single-agent treatments.

Conclusions: IKZF1 represses BCL-2 in T-ALL, and targeting the CK2-IKZF1 axis with CX-4945 and venetoclax offers a promising therapeutic strategy, showing enhanced efficacy and potential as a novel treatment approach for T-ALL.

Objective: This study aims to explore the effects of silencing Zic family member 5 (ZIC5) on glucose metabolism and disulfidptosis in lung adenocarcinoma (LUAD) cells.

Methods: Data from The Cancer Genome Atlas (TCGA) was used to analyze ZIC5 expression in LUAD and its association with patient outcomes. ZIC5 was silenced in A549 and H1299 cells using siRNA. The expression of ZIC5 mRNA and protein was assessed by qRT-PCR and Western blot. Cell proliferation was evaluated through CCK-8 and 5-ethynyl-2'-deoxyuridine (EdU) assays, while glucose uptake, lactate production, and ATP levels were measured to assess energy metabolism. Seahorse XF analysis was used to evaluate extracellular acidification rate (ECAR) and oxygen consumption rate (OCR). Disulfidptosis was assessed through NADP⁺/NADPH ratio, glutathione (GSH) content, GSSG/GSH ratio, and immunofluorescence staining.

Results: ZIC5 is highly expressed in LUAD and is associated with poor patient prognosis. Silencing ZIC5 significantly reduced its mRNA and protein levels in A549 and H1299 cells, markedly inhibited cell proliferation, and led to significant decreases in glucose uptake, lactate production, ATP levels, ECAR, and OCR. Additionally, silencing ZIC5 resulted in an increased NADP⁺/NADPH ratio, decreased GSH levels, and a reduced GSSG/GSH ratio, alongside classic disulfidptosis features.

Conclusion: ZIC5 plays a crucial role in promoting LUAD cell proliferation and energy metabolism while inhibiting disulfidptosis. Silencing ZIC5 markedly suppresses these processes, indicating its potential as a therapeutic target in LUAD.

With over 60,000 cases diagnosed in women annually, ductal carcinoma in situ (DCIS) is the most common form of pre-invasive breast cancer in the US. Despite standardized therapy, under-treatment and over-treatment are prevailing concerns. By understanding the mechanisms regulating DCIS progression, we may develop tailored strategies to improve treatment. CCL2/CCR2 and HGF/MET signaling pathways are upregulated in breast cancers. Our studies indicate that these pathways cooperate to promote DCIS progression and metabolism. DCIS and IDC tissues were immunostained for CCL2 and HGF expression. DCIS.com and HCC1937 cells were analyzed for cell proliferation through PCNA immunostaining, apoptosis through cleaved caspase-3 immunostaining, and invasion through Matrigel transwell assays. AKT, AMPK, p42/44MAPK and PKC activities were analyzed in vitro through immunoblot and pharmacologic inhibition. CCL2 and HGF-mediated metabolism were analyzed by LC-MS. Glucose uptake and lactate production were measured biochemically. CCR2 and MET were targeted in breast xenografts through CCR2 knockout and treatment with Merestinib. Significant associations between CCL2 and HGF were detected in DCIS and IDC tissues. CCL2 and HGF co-treatment enhanced breast cancer cell growth, survival, and invasiveness over individual CCL2 or HGF treatment. These CCL2/HGF-mediated phenotypes were associated with metabolic changes including glycolysis and increased AKT, AMPK, p42/44MAPK and PKC signaling. CCL2/HGF-mediated glycolysis was reduced with AKT, AMPK and p42/44MAPK inhibition. CCR2 knockout combined with Merestinib treatment inhibited growth, survival, and stromal reactivity of breast xenografts more than CCR2 or MET targeting alone. CCL2/CCR2 and HGF/MET cooperate to enhance breast cancer progression and metabolic reprogramming.

To explore the feasibility, safety, and effectiveness of brachytherapy of locally advanced bladder cancer, clinical data of 86 patients with locally advanced bladder cancer treated in the Department of Urology Surgery, Shanxi Provincial Cancer Hospital, between January 2015 and June 2019 were analyzed retrospectively. The patients were categorized into the study (n = 45) and control (n = 41) groups according to the treatment methods. Patients in the study group were treated with brachytherapy (intraoperative implantation of radioactive particles) + neoadjuvant chemotherapy (NAC), and those in the control group were treated with NAC. Patients in both groups underwent radical cystectomy (RC) + pelvic lymph node dissection. Postoperative pathological examinations proved that patients in both groups had urothelial carcinoma at stage pT₃-pT₄. The endpoints included 3-y locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), disease-free survival (DFS), overall survival (OS), and adverse events after treatment. The efficacy and safety of interstitial implantation of radioactive particles for the treatment of locally advanced bladder cancer were assessed. The patients were followed up for 9-42 months. The 3-y LRFS was significantly higher in the study group (88.9%) than in the control group (60.9%) (p = .003). The 3-y DMFS in the study group (71.1%) and the control group (73.2%) was statistically similar (p = .945). The 3-y DFS and OS were not statistically significant between the two groups (DFS: study group 64.4% vs. control group 51.2%, p = .073; OS: study group 66.7% vs. control group 58.5%, p = .180). Local shifting of the particles was detected in three patients at 1 week to 1 month after the operations in the study group, but no related complications were observed. Blood events (anemia, leukocytopenia, and thrombocytopenia), liver and renal dysfunction, vomiting, diarrhea, and weakness were the major adverse reactions, which were alleviated after symptomatic treatments. The results have not statistically significant differences between the two groups in major adverse reactions. Compared to the NAC group, brachytherapy + NAC significantly prolongs the LRFS of patients with locally advanced urothelial bladder carcinoma who underwent RC + pelvic lymph node dissection. This surgery increases the LRFS, develops better personalized treatment plans, and improves treatment effectiveness. In addition, the treatment is safe and effective, with only limited adverse effects.

Sufficient MHC-I expression on cancer cells is essential for the recognition and killing of cancer cells by immune effector cytotoxic T-lymphocyte (CTL). An important mechanism of cancer immune escape is loss or down-regulation of MHC-I. This is frequently associated with reduced expression of NOD-like receptor (NLR) caspase recruitment domain containing protein 5 (NLRC5), genetically and epigenetically. NLRC5, a regulator of MHC-I, has been identified as a potential target of miR-4319 due to its complementary binding site for miR-4319, according to prediction by TargetScan (http://www.targetscan.org/). Inhibition of miR-4319 by IFN-γ (known as MHC-I increasing agent) to upregulate NLRC5 with upregulation of MHC-I in MHC-I-deficient breast cancer cells, however, remains unclear. After treatment with IFN-γ, miR-4319 was detected with qRT-PCR; NLRC5 protein was detected with western-blot; and MHC-I mRNA and protein were detected with qRT-PCR and western-blot, respectively. It was found statistically that miR-4319 was lower and NLRC5 protein was higher in groups of 50 U/ml and 100 U/ml IFN-γ, and MHC-I mRNA and protein were higher in all groups of different concentrations of IFN-γ, except for HLA-A protein in 25 U/ml IFN-γ group, with dose dependent tendency, compared with the control group. IFN-γ inhibits miR-4319 and upregulates NLRC5, thereby enhancing expression of MHC-I in SKBR3 breast cancer cells, while limitations include the absence of functional rescue experiments and in vivo validation. Along with direct cytotoxicity on tumor cells, IFN-γ's immunomodulatory effect strengthens tumor immunogenicity, counteracts immune evasion mechanisms, and potentially improves the efficacy of cancer immunotherapy.

Purpose: Metastatic castration-resistant prostate cancer (mCRPC) remains a significant therapeutic challenge and a leading cause of cancer-related mortality in men. PARP inhibitors like Olaparib are effective in homologous recombination repair (HRR)-deficient tumors, but resistance often arises through DNA repair restoration. This study explores the role of the structure-specific endonuclease subunit SLX1, a catalytic subunit of the SLX1-SLX4 endonuclease complex, in Olaparib resistance.

Methods: Data from The Cancer Genome Atlas (TCGA) were used for expression and survival analyses. The CRPC cell line DU145, which harbors BRCA1 and BRCA2 mutations, was used as a cell model for both in vitro and in vivo studies.

Results: Elevated SLX1A expression in prostate cancer tissues was associated with significantly reduced progression-free and overall survival. SLX1 protein was upregulated in androgen-resistant prostate cancer cell lines (DU145, 22RV1, PC3) and further increased in Olaparib-resistant DU145 (DU145-OR) cells. Silencing SLX1 via shRNA enhanced Olaparib sensitivity, reducing colony formation and increasing DNA damage and apoptosis in DU145 and DU145-OR cells. Mechanistically, SLX1 knockdown disrupted SLX4 interactions with critical DNA repair proteins (ERCC1-XPF, PLK1, and TOPBP1), impairing DNA repair complex stability. In vivo, SLX1-silenced DU145 xenografts treated with Olaparib showed significantly reduced tumor growth with decreased Ki-67 expression and increased apoptosis/necrosis compared to controls.

Conclusion: This study highlights SLX1 as both a prognostic marker and potential therapeutic target to enhance PARPi efficacy in advanced prostate cancer. Targeting SLX1 may be a promising strategy to overcome Olaparib resistance in mCRPC patients with homologous recombination deficiency.

KRAS mutations are common in non-small cell lung cancer (NSCLC) and are associated with patient prognosis; however, targeting KRAS has faced various difficulties. Currently, immunotherapy, chemotherapy, and chemoimmunotherapy play pivotal roles in the first-line treatment of KRAS-mutated NSCLC. Here, we summarize the current evidence on first-line therapies and compare the treatment outcomes and biomarkers for different regimens. KRAS inhibitors and other emerging alternative treatments are also discussed, as combining these drugs with immunotherapy may serve as a promising first-line treatment for KRAS-mutated NSCLC in the future. We hope that this review will assist in first-line treatment choices and shed light on the development of novel agents for KRAS-mutated NSCLC.