Translational cancer research最新文献

Background: Transfer RNA-derived small RNAs (tsRNAs) have been shown to participate in tumorigenesis and progression of human cancers. We aimed to identify dysregulated tsRNAs in esophageal cancer (EC) and uncover the underlying mechanisms.

Methods: tsRNA profiles for EC were downloaded from MINTbase. We also detected expression levels of tsRNAs in EC tissues using tsRNA sequencing and real-time quantitative polymerase chain reaction (RT-qPCR). The functional roles of tRF-29-86J8WPMN1EJ3 in EC were investigated by transfecting EC cell lines with mimics of tRF-29-86J8WPMN1EJ3 and assessing phenotypes through colony formation, wound healing, and Transwell assays.

Results: Totally, 210 differentially expressed tsRNAs were identified from MINTbase. In addition, 40 EC patients were recruited, and four paired EC and adjacent normal tissues were randomly selected for tsRNA sequencing, identifying 159 dysregulated tsRNAs, which were intersected with the 210 tsRNAs from MINTbase, obtaining three tsRNAs: tRF-28-P4R8YP9LOND5, tRF-29-86J8WPMN1EJ3, and tRF-29-P4R8YP9LONHK. Their expression levels were validated in 40 paired tissues. All three tsRNAs were up-regulated in EC tissues, and their high expression levels were associated with shorter overall survival (OS) in EC patients. In vitro experiments indicated that overexpression of tRF-29-86J8WPMN1EJ3 could promote proliferation, migration, and invasion of EC cell lines.

Conclusions: In conclusion, we presented the expression characteristics of tsRNAs in EC and identified three up-regulated tsRNAs in EC tissues. Lower expression levels of these tsRNAs were associated with better OS in EC patients. Additionally, tRF-29-86J8WPMN1EJ3 promotes the proliferation, migration, and invasion of EC cells.

Background: Hepatocellular carcinoma (HCC) represents one of the most life-threatening malignancies globally. Despite significant advancements in the treatment of HCC in recent years, therapeutic outcomes remain unsatisfactory, particularly for patients with advanced, inoperable HCC. Thus, there is an urgent need to identify novel therapeutic targets and develop combination therapies to enhance treatment efficacy. The aim of this study is to elucidate the role and mechanism of solute carrier family 25 member A3 (SLC25A3) in HCC.

Methods: In this study, we examined the expression profiles and prognostic implications of mitochondrial-related gene sets in HCC using data from The Cancer Genome Atlas (TCGA) database. Among these genes, SLC25A3, a mitochondrial membrane protein, was found to be significantly overexpressed in HCC and associated with poor prognosis. To explore the potential role of SLC25A3 in HCC, we conducted analyses of clinical samples and performed in vivo and in vitro experiments. The underlying mechanisms were further investigated using multi-omics sequencing techniques.

Results: The experimental results confirmed that SLC25A3 plays an oncogenic role in hepatocarcinogenesis, potentially by inducing mitochondrial dysfunction. Further multi-omics analysis revealed that the oncogenic effects of SLC25A3 in HCC may be mediated through its regulation of mitochondrial function and chromatin remodeling.

Conclusions: These findings offer valuable insights for identifying potential therapeutic targets for HCC.

Background: Cisplatin resistance represents a major clinical challenge in osteosarcoma (OS), often leading to treatment failure and poor patient prognosis. The underlying molecular mechanisms are complex and incompletely understood. This study investigates the role of the RNA methyltransferase methyltransferase-like 3 (METTL3) and its associated N6-methyladenosine (m6A) modification in driving cisplatin resistance, with a specific focus on the METTL3-m6A-proliferating cell nuclear antigen (PCNA) regulatory axis as a potential therapeutic target.

Methods: Cisplatin-resistant human OS cell lines (MG-63/DDP, U2OS/DDP) were used. The effects of the selective METTL3 inhibitor STM2457, both alone and in combination with cisplatin, on cell viability, apoptosis, and migration were evaluated using Cell Counting Kit-8 (CCK-8) assay, immunofluorescence staining for cleaved Caspase-3, and vimentin expression, respectively. Mechanistic investigations included quantification of global m6A levels, analysis of PCNA messenger RNA (mRNA) stability via actinomycin D assay, and western blot for protein expression. Functional roles were validated using small interfering RNA-mediated PCNA knockdown and plasmid-based PCNA overexpression. Drug interaction was analyzed using the combination index (CI) method.

Results: STM2457 monotherapy significantly and dose-dependently suppressed cell proliferation and migration in cisplatin-resistant OS cells. Furthermore, STM2457 demonstrated strong synergistic effects with cisplatin (CI <1), markedly enhancing apoptosis induction. At the molecular level, STM2457 inhibited METTL3 catalytic activity, leading to a significant reduction in global m6A RNA methylation. This resulted in the destabilization of PCNA mRNA and a consequent decrease in PCNA protein levels. Knockdown of PCNA effectively mimicked the anti-tumor effects of STM2457, whereas forced overexpression of PCNA attenuated the efficacy of STM2457 and partially restored the cisplatin-resistant phenotype.

Conclusions: Our findings demonstrate that STM2457 overcomes cisplatin resistance in OS by targeting the METTL3-m6A-PCNA axis, thereby disrupting a key DNA repair and cell survival pathway. Pharmacological inhibition of METTL3 represents a novel and promising epigenetic strategy for resensitizing chemoresistant OS, supporting its potential for future clinical development.

Background: Lung cancer has the highest incidence among malignant tumors, and its high degree of metastasis and invasion, tendency to metastasis, and mortality rate are the key factors leading to treatment failure and poor prognosis. Tumor-associated macrophages (TAMs), which often exhibit an M2-polarized phenotype, are known to promote tumor progression. Notably, the chemokine CXCL9 has emerged as a critical regulator that can inhibit M2 macrophage polarization, thereby potentially suppressing tumor growth. This study combined clinical sample testing and prognostic analysis with cell behaviorology and molecular biology to systematically investigate the role and regulatory mechanism of CXCL9 in the tumor microenvironment of lung cancer.

Methods: THP-1 cells were induced to differentiate into M1 and M2 macrophages. The effects of M2 macrophages on the proliferation, migration, and invasion of A549 lung adenocarcinoma cells were detected via Cell Counting Kit-8 cell viability, scratch-wound, and Transwell invasion assays. The effects of CXCL9 on M2 macrophage function and the expression of related proteins were detected via enzyme-linked immunosorbent assay, reverse transcription polymerase chain reaction, and Western blotting.

Results: CXCL9 significantly inhibited the promoting effects of M2 macrophages on the proliferation, migration, metastasis and invasion of A549 cells. Specifically, CXCL9 inhibited M2 macrophage polarization by reducing the expression of surface markers CD16, CD32, and CD206. CXCL9 also inhibited the expression of VEGF-C, MMP9, and MMP2, thereby inhibiting tumor cell invasion and metastasis. Moreover, CXCL9 inhibited the activation of the ERK and AKT signaling pathways, further inhibiting tumor cell proliferation and invasion.

Conclusions: CXCL9 inhibits the proliferation, migration, metastasis and invasion of lung cancer cells by inhibiting M2 macrophage polarization and function, indicating that CXCL9 may serve as a potential therapeutic target for lung cancer.

Background: An aberrant expression of the voltage-gated potassium (Kv) channel family has been verified in a variety of tumors, which can contribute to tumor proliferation and migration by regulating the cell cycle, suppressing apoptosis, facilitating the epithelial-mesenchymal transition (EMT), and activating downstream tumor-associated pathways. Kv3.3 is encoded by the Kv channel subfamily C member 3 (KCNC3). Previous studies on KCNC3 focused primarily on nervous system diseases rather than tumors. Therefore, our aim is to explore the potential biological roles and clinical significance of KCNC3 in the field of oncology.

Methods: This study was conducted to investigate the differential expression, prognostic value, immune microenvironment (IME) signature, and biological functions of KCNC3 in pan-cancer in The Cancer Genome Atlas (TCGA), Cancer Cell Line Encyclopedia (CCEL), and Tumor-Immune System Interaction Database (TISIDB) and to validate the findings in colorectal cancer (CRC).

Results: The expression of KCNC3 was higher in various cancer tissues than in normal tissues, which was associated with the tumor stage and unfavorable prognosis. The KCNC3 expression correlated significantly with immune cell infiltration, IME signature scores, microsatellite instability (MSI), chemokines, tumor mutation burden (TMB), and immune checkpoints (ICs). Moreover, the drug sensitivity analysis using CellMiner revealed the association of KCNC3 with the sensitivity to a variety of drugs. The up-regulation of voltage-gated potassium channel KCNC3 in CRC and its association with unfavorable prognosis were revealed by immunohistochemistry (IHC).

Conclusions: KCNC3 can facilitate the pro-tumorigenic transformation of the tumor IME, contributing to the proliferation of tumors, especially CRC. KCNC3 can act as a novel prognostic and immune-related biomarker in CRC.

Background: Perchlorate is a persistent environmental contaminant and endocrine disruptor that inhibits iodine uptake through the sodium iodide symporter. While its thyroid toxicity is well recognized, evidence regarding its association with malignancies of endocrine-related tissues is limited. This study aimed to investigate the relationship between urinary perchlorate and the occurrence of thyroid cancer and pancreatic cancer in a nationally representative U.S. adult population.

Methods: Data from 20,316 adults in the National Health and Nutrition Examination Survey (NHANES; 2003 to 2018) were analyzed. Urinary perchlorate was measured using ion chromatography with electrospray tandem mass spectrometry. Urinary perchlorate levels were creatinine-corrected before analysis. Weighted multivariable logistic regression was applied to assess associations with self-reported physician-diagnosed thyroid cancer and pancreatic cancer. Bayesian correlation analysis was performed for pancreatic cancer and thyroid cancer due to the small number of cases. Restricted cubic spline models were used to explore dose-response relationships.

Results: The normalized urinary perchlorate level was significantly associated with both thyroid (P=0.041) and pancreatic cancer (P<0.001). This association remained significant across models when analyzed by quartiles [thyroid cancer: odds ratio (OR) =3.81, 95% confidence interval (CI): 1.26-11.5, P=0.02; pancreatic cancer: OR =13.4, 95% CI: 1.13-159, P=0.04]. Bayesian analysis provided robust evidence supporting these associations (Bayes factor: thyroid cancer =139.525; pancreatic cancer =176.853). No clear dose-response relationship was observed for either cancer type.

Conclusions: Perchlorate exposure was associated with both thyroid and pancreatic cancers. This study provides evidence supporting its potential role in endocrine-related carcinogenesis and underscores the need for further research and exposure-reduction strategies.

Background: Large cell neuroendocrine carcinoma (LCNEC) accounts for approximately 3% of lung cancers and carries a poor prognosis. For early-stage, node-negative disease classified as T1-2N0M0 by the 9^th edition tumor, node, metastasis (TNM) staging system, the role of adjuvant chemotherapy following surgical resection remains controversial due to limited evidence from randomized trials. Our research aims to evaluate the effectiveness of adjuvant chemotherapy in this specific patient population using a large national database.

Methods: We sourced data of patients who were diagnosed with LCNEC at the T1-2N0M0 stage and had undergone surgery, focusing on the time frame from the start of 2004 to the end of 2015, using the Surveillance, Epidemiology, and End Results (SEER) database as our resource. In order to comprehensively evaluate the cancer-specific survival (CSS) and overall survival (OS) across different groups, we implemented a multi-faceted statistical approach, encompassing subgroup analyses, propensity score matching (PSM) techniques, and Kaplan-Meier (K-M) survival curves. Additionally, we employed the Cox Proportional-Hazards model to pinpoint standalone predictors of outcomes in LCNEC staged as T1-2N0M0.

Results: Of the 582 T1-2N0M0 LCNEC patients studied, 473 (81%) patients underwent surgery alone. Before and after applying propensity score adjustments, we found no notable variance in OS and CSS when comparing the surgery-only cohort to the group that received adjuvant chemotherapy. Exploratory subgroup analyses suggested potential heterogeneity in treatment associations, though biological plausibility was uncertain. Cox regression identified middle tumor location, segmentectomy, age ≥65 years, and zero regional nodes examined as independent prognostic factors (P<0.05).

Conclusions: According to the 9^th edition of the American Joint Committee on Cancer (AJCC) staging system, adjuvant chemotherapy does not provide significant survival benefits for the overall T1-2N0M0 LCNEC population. Exploratory subgroup analyses suggested potential heterogeneity in treatment associations; however, given the retrospective design and inherent limitations of SEER data (lacking performance status, comorbidities, recurrence data, and detailed chemotherapy information), these hypothesis-generating findings require prospective validation before informing clinical practice.

Background: Small cell lung cancer with brain metastasis (SCLC-BM) is associated with a poor prognosis and a high probability of death. However, to date, few models exist to predict early death (ED) in patients with SCLC-BM. This study aimed to construct nomograms to predict ED in patients diagnosed with SCLC-BM.

Methods: The data of SCLC-BM patients were extracted from the Surveillance, Epidemiology, and End Results (SEER) database (2010-2015). The patients were randomly divided into training and test cohorts at a 7:3 ratio. Univariate regression was first performed to assess the significance of each variable. Least absolute shrinkage and selection operator (LASSO) regression was then applied to identify the most critical and minimum prognostic factors. Subsequently, a multivariate analysis was conducted to develop two nomograms to predict all-cause early death (ACED) and cancer-specific early death (CSED). The calibration and discriminative abilities of these nomograms were evaluated using receiver operating characteristic (ROC) curves and calibration curves. A decision curve analysis (DCA) was employed to assess the clinical applicability of the models.

Results: Primary site, regional lymph node stage (N stage), race, age, tumor size, radiotherapy, and chemotherapy were identified as independent predictors of ACED, while race, age, tumor size, radiotherapy, and chemotherapy were identified as independent predictors of CSED. Nomograms were developed based on these variables. The area under the curve (AUC) values of the ROC curves for ACED were 0.837 in the training cohort and 0.813 in the test cohort, while those for CSED were 0.794 and 0.783, respectively. Based on the performance of the ROC, calibration, and DCA curves, these predictive models demonstrated favorable efficacy.

Conclusions: This study developed nomograms to predict ACED and CSED in patients with SCLC-BM. The nomograms demonstrated clinical utility in ED prediction in the post-treatment planning period, and thus could assist oncologists in identifying high-risk patients after initial treatment planning has been established.

Background: Adrenocortical carcinoma (ACC), an extremely uncommon and highly aggressive endocrine malignancy, has few therapeutic options and is associated with a poor prognosis. This study aimed to evaluate the prognostic significance of preoperative neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in a Chinese cohort with ACC and to determine the influence of cortisol secretion on these inflammatory markers.

Methods: We retrospectively analyzed 45 patients with ACC treated at a single institution from 1985 to 2020. Baseline clinicopathological data, preoperative NLR and PLR values, and follow-up information were collected. The NLR cutoff of 3.9 was selected a priori based on previously published studies of ACC. Disease-specific survival (DSS) was assessed via Kaplan-Meier and Cox proportional hazards models. Patients were stratified according to the presence of Cushing's syndrome (CS) in order to specifically assess the influence of hypercortisolemia.

Results: A total of 33 disease-specific deaths occurred during the follow-up period. Multivariate analysis indicated that the independent predictors of worse DSS were NLR >3.9 [hazard ratio (HR) =4.12, 95% confidence interval (CI): 1.25-13.61, P=0.02], an elevated Ki-67 index (HR =1.04, 95% CI: 1.01-1.07, P=0.01), and advanced European Network for the Study of Adrenal Tumors (ENSAT) stage (III-IV) (HR =45.64, 95% CI: 2.88-724.60, P=0.007). Although NLR was significantly higher in patients with CS than without CS (5.07 vs. 3.70, P=0.047), CS itself was not an independent prognostic factor. Notably, in patients without CS, elevated NLR correlated with aggressive features (local invasion, vascular invasion, and distant metastasis) but not with independent survival prognosis.

Conclusions: Preoperative NLR >3.9 may serve as a simple and accessible prognostic marker for DSS in Chinese patients with ACC. Its predictive value is influenced by both tumor-induced inflammation and cortisol secretion, highlighting its utility in risk stratification beyond traditional factors.