Molecular Carcinogenesis最新文献

Oral squamous cell carcinoma (OSCC) is a life-threatening disease that ranks sixth amongst the most common human cancers worldwide. In most cases, OSCC development is preceded by oral premalignant disorders (OPMDs). There is an urgent need for more biomarker studies that will aid in early detection, diagnosis, and treatment of OPMD to prevent their transformation to OSCC. Leucine rich repeats and immunoglobulin like domains 1 (LRIG1) are known to negatively regulate EGFR expression. Little is known about the significance of LRIG1 in oral cancer pathogenesis. In a retrospective study, immunohistochemical analysis of EGFR and LRIG1 was carried out in 212 archival oral tissues (100 OSCC, 87 OPMD, and 25 normal), correlated with clinicopathological parameters and disease outcome over 62 months for OSCC patients. Further, gene expression for EGFR and LRIG1 was also evaluated in 160 tissue samples. Significant increase in EGFR in OSCC tissue was observed compared to controls, while LRIG1 levels were found to be downregulated in OSCC and OPMD cases compared to normal tissues (p < 0.05). Kaplan-Meier analysis of patients stratified to high and low LRIG1 expression showed significantly different overall survival (p < 0.05, median survival 1397 and 561 days, respectively). A unique translational impact of our study is that it provides clinical evidence for the potential of LRIG1 downregulation as predictor of poor prognosis in OSCC. These preliminary findings support further research to validate LRIG1 based prognostic tools for oral cancers.

Cutaneous squamous cell carcinoma (cSCC) is a malignant skin cancer which is derived from epidermal keratinocytes, and long-term exposure to ultraviolet rays is its main risk factor. Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) is a crucial gene for the formation and stability of collagen intermolecular cross-links, being vital in the development of cancer. Nevertheless, the interaction between cSCC and PLOD2 has not been elucidated. Here, we found PLOD2 upregulated in human cSCC. Its knockdown in cSCC cells suppressed proliferation, migration, invasion, and angiogenesis while inducing apoptosis and cell cycle arrest; overexpression promoted these malignant phenotypes. In mouse xenografts, PLOD2 knockdown inhibited tumor growth and collagen deposition. Furthermore, in a DMBA/TPA-induced carcinogenesis model, topical PLOD2 inhibition by minoxidil suppressed tumor development as well. Mechanistically, our studies revealed that PLOD2 acts as a key downstream effector of STAT3 to activate ERK and AKT signaling evidenced by rescue experiments. As a result, our study not only establishes the STAT3/PLOD2/ERK-AKT axis as a key driver of cSCC but also identifies the clinically approved drug minoxidil as a potent PLOD2 inhibitor, demonstrating immediate promise as a repurposed therapeutic agent.

Tumor-associated macrophages (TAMs) are critical contributors to cancer progression and are often recruited by cancer cells to support a pro-tumorigenic microenvironment. Integrin αvβ3 is a known driver and marker of cancer stem-like properties, including tumor initiation, in various epithelial cancers. We have previously shown a positive correlation between αvβ3 expression and TAM infiltration across multiple tumor types; however, the mechanistic link remains undefined. Here, we demonstrated that integrin αvβ3 expression in non-small cell lung cancer (NSCLC) cells is both necessary and sufficient to drive TAM accumulation. In orthotopic murine and human NSCLC models, ectopic integrin αvβ3 expression increased TAM infiltration independently of T cells, whereas genetic deletion of integrin β3 significantly reduced TAM numbers and tumor burden. Mechanistically, integrin αvβ3 promotes glutamine secretion from NSCLC cells, which enhances the survival and/or differentiation of bone marrow-derived macrophages. Functionally, TAMs are essential for the elevated tumor-initiating capacity of αvβ3+ cancer cells, as macrophage depletion abolished this effect. Together, our findings uncover a novel mechanism by which NSCLC cells remodel the tumor microenvironment via αvβ3-mediated glutamine secretion, promoting TAM enrichment and tumor initiation. Targeting this axis may offer therapeutic benefits in αvβ3-expressing cancers.

Functional DNA methylation abnormalities are a hallmark of human cancers and may be a promising biomarker for their early diagnosis. Moreover, the largest methylation differences can improve the sensitivity of noninvasive diagnoses of solid tumors. We combined whole-genome bisulfite sequencing (WGBS) and mRNA-seq data from 33 paired hepatocellular carcinoma (HCC) and adjacent tissues to identify methylation markers that could be used for noninvasive diagnosis in blood samples. Methylation markers were selected according to the following criteria: differentially methylated regions (DMR) located in the promoter region with large differences in methylation (Δβ > 0.3) and inverse correlation with matched gene expression (cor < -0.3). Cell-free DNA (cfDNA) from 48 patients with HCC and 24 normal participants was used to verify the performance of meTSPYL5 using qMSP. Integrated WGBS and transcriptomic data analysis identified eight target promoter hyper-DMRs. After confirming the WGBS profiles of genes in peripheral blood mononuclear cells, meTSPYL5 was selected to further verify the plasma cfDNA samples by qMSP. The results of plasma validation showed that the methylation detection of meTSPYL5 was sensitive for identifying HCC, with a sensitivity and specificity of 85.4% and 100%, respectively. Pan-cancer analysis found that the methylation level of TSPYL5 was elevated in multiple cancer types, indicating that it lacks cancer-type specificity; however, this result does not affect its application value in monitoring high-risk populations of HCC. By analyzing and integrating all available high-throughput epigenomic and transcriptomic data from human HCC tissues, we identified eight regions as potential diagnostic biomarkers for HCC. Integrative analyses of epigenomic and transcriptomic data provide an efficient method to identify diagnostic biomarkers for human cancers. Methylated TSPYL5 in plasma is a promising biomarker for the detection and screening of HCC.

Chemotherapy remains the frontline treatment strategy for triple-negative breast cancer (TNBC). However, the aggressive nature of TNBC, due to metabolic reprogramming, is often associated with chemoresistance, which limits treatment efficacy. Herein, we investigated the impact of altered lipid homeostasis, in particular, the fatty acid β-oxidation (FAO) pathway, during doxorubicin (Dox)-induced chemoresistance and its effect on drug retention and efficacy in TNBC cells. Results indicate that Dox-induced chemoresistance in MDA-MB-231 cells and an in vivo Dox-resistance breast cancer model in SCID mice are associated with a marked upregulation of FAO. Intriguingly, the basal levels of carnitine palmitoyltransferase 1 (CPT1; a rate-limiting enzyme of FAO), CD36, (a fatty acid translocase), FAO-related gene transcript levels, and acetyl-CoA production were significantly elevated with increased degree of Dox resistance. These changes were paralleled by enhanced uptake of fatty acids and their oxidation. Dox-resistance in TNBC cells was associated with enhanced mitochondrial respiration, possibly due to increased activities of complex I and IV. Conversely, inhibition of CPT1 by etomoxir caused increased intracellular Dox retention, leading to Dox-induced cytotoxicity and attenuating the invasiveness of TNBC cells. Importantly, FAO-derived ATP levels, compared to glucose-derived ATP, seem to enhance the invasiveness of Dox-resistant cells. Mechanistically, Dox-resistance potentiated FAO via CREB activation, which in turn led to the enhancement of the PGC1α/PPARα/CD36-CPT1 axis. Taken together, Dox-resistance reprograms cellular metabolism towards FAO regulatory circuit sustaining the mitochondrial bioenergetics, promoting drug efflux, and accentuating breast cancer progression. Based on these findings, it is possible that FAO inhibitors effectively combat drug-induced TNBC chemoresistance.

Larynx cancer, a malignant tumor originating from the epithelial cells of the larynx, remains a significant clinical challenge. Although both N⁵-methylcytosine (m⁵C) modification and glycolysis are critically implicated in cancer progression, their functional interplay in larynx cancer is not well defined. This study aims to elucidate the mechanism through which m⁵C modification influences larynx cancer progression via glycolysis. We performed bioinformatics analysis on the GSE59102 data set to identify m⁵C-related differentially expressed genes (DEGs) between larynx cancer and normal tissues. Functional assays, including CCK-8, EdU staining, glucose uptake, lactate production, and extracellular acidification rate (ECAR) measurements, were conducted to assess cell viability, proliferation, and glycolysis in larynx cancer cell lines (AMC-HN-8 and TU686). The underlying mechanism was further investigated using methylated RNA immunoprecipitation (MeRIP), RNA immunoprecipitation (RIP), and dual-luciferase reporter assays. In vivo validation was obtained through xenograft tumor models and immunohistochemistry. Our results demonstrated that the m⁵C methyltransferase NOP2 was significantly upregulated in larynx cancer. Knockdown of NOP2 inhibited cell viability, proliferation, and glycolysis in larynx cancer cells, and attenuated tumor growth in nude mice. Mechanistically, NOP2 silencing reduced the m⁵C modification on TPI1 mRNA, thereby decreasing its stability. Furthermore, overexpression of TPI1 rescued the impaired glycolysis in larynx cancer cells caused by NOP2 knockdown. In summary, this study reveals that NOP2 facilitates larynx cancer progression by enhancing glycolysis through m⁵C-mediated stabilization of TPI1 mRNA. Our findings uncover the NOP2/m⁵C/TPI1 axis as a novel therapeutic target and provide new insights into RNA methylation-driven metabolic reprogramming in larynx cancer.

Cisplatin is one of the most effective chemotherapeutic agents used in the treatment of ovarian cancer. However, the frequent development of cisplatin resistance remains a significant limitation, leading to therapeutic failure and poor patient outcomes. Cisplatin cytotoxicity is attributed to the generation of toxic DNA lesions, which can be recognized and processed by a variety of proteins, including the high mobility group box 1 (HMGB1) protein. HMGB1 is a multifunctional protein, which is involved in chromatin remodeling and multiple DNA damage repair pathways. In this study, we investigated the role of HMGB1 in modulating cisplatin sensitivity in human ovarian cancer cells. Using cisplatin-sensitive and cisplatin-resistant human ovarian cancer cell lines, we employed siRNA-mediated HMGB1 knockdown to assess its impact on the cellular responses to cisplatin treatment. In clonogenic survival assays, HMGB1 depletion resulted in a significant reduction in colony formation in cisplatin-resistant cells upon cisplatin exposure, compared with nontargeting siRNA treated cells. Additionally, HMGB1 inhibition significantly enhanced cisplatin-induced apoptosis in the cisplatin-resistant cells. Mechanistically, HMGB1-depleted cells exhibited altered DNA damage responses via modulation of ATM/CHK2 and ATR/CHK1 activity following cisplatin treatment. Notably, DNA immunoblot and modified alkaline comet assay results demonstrated that HMGB1 depletion stimulated cisplatin-DNA adduct formation and impaired the removal of cisplatin-DNA adducts, particularly in the cisplatin-resistant cells. Collectively, these findings uncover novel functions of HMGB1 in mediating cisplatin sensitivity, emphasizing its potential as a therapeutic target to overcome cisplatin resistance in ovarian cancer.

Retraction: M. Chatterjee, S. Das, K. Roy, and M. Chatterjee, "Overexpression of 5-lipoxygenase and Its Relation With Cell Proliferation and Angiogenesis in 7,12-Dimethylbenz(α)anthracene-Induced Rat Mammary Carcinogenesis," Molecular Carcinogenesis 52, no. 5 (2013): 359-369. https://doi.org/10.1002/mc.21858. The above article, published online on 28 December 2011 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by Wiley Periodicals LLC. A third party reported that portions of the image in Figure 2B had been duplicated and manipulated from another article by some of the same authors [Chatterjee et al. 2011 (https://doi.org/10.1016/j.ejphar.2011.06.039)]. Additionally, the third party reported that the beta-actin band in Figure 3A had been duplicated from an alpha-tubulin band presented in Chatterjee et al. 2011. Further investigation by the publisher found that Figure 5B had been duplicated from another article by different authors [von Euler et al. 2004 (https://doi.org/10.1016/j.bioelechem.2003.10.008)] and also found evidence of additional image manipulation in Figures 3A and 3C. The authors responded to an inquiry by the publisher. However, the authors were unable to provide original, unmodified data or images for the experiments reported in the article and were unable to provide a sufficient explanation for the findings of the investigation. The retraction has been agreed to because evidence of image duplication and manipulation fundamentally compromises the reported conclusions. The authors disagree with the retraction.

NAT10, an essential enzyme catalyzing RNA ac⁴C modification, is recognized as a critical regulator of tumorigenesis and progression. This study investigates the role and underlying molecular mechanisms of NAT10 in breast cancer. We found that NAT10 is significantly overexpressed in breast cancer tissues compared to adjacent normal tissues, exhibiting high diagnostic accuracy (AUC = 0.9702, p < 0.001). Consistently, NAT10 expression was also elevated in breast cancer cell lines. Knockdown of NAT10 potently inhibited cell viability, glycolysis (as indicated by reduced glucose uptake, lactate production, and ECAR), and metastatic potential (manifested as suppressed migration and invasion) in breast cancer cells. Mechanistically, NAT10 regulated TRAF6 expression and stability through ac⁴C modification; NAT10 knockdown led to reduced ac⁴C enrichment on TRAF6 mRNA and accelerated its degradation. Rescue experiments confirmed that TRAF6 overexpression partially reversed the inhibitory effects of NAT10 knockdown on glycolysis and metastasis. In vivo, NAT10 knockdown significantly suppressed tumor growth in nude mice, which was associated with reduced expression of Ki67 and TRAF6 in tumor tissues. Collectively, our findings highlight NAT10 as a key regulator of breast cancer progression via ac⁴C-mediated TRAF6 modulation, suggesting it as a promising therapeutic target for breast cancer therapy.

Gastric cancer (GC) is the fifth most common type worldwide, representing a public health problem. Among the genes related to this tumorigenesis, the family of matrix metalloproteinases (MMPs), essential regulators of the extracellular matrix (ECM), stand out for their involvement in the development and progression of GC. Therefore, we aimed to evaluate MMP gene expression variation, its relationship with clinicopathological factors and its transcriptome-wide associations. To this end, RNAseq, correlation network, and biological pathway enrichment analyses were performed on tumor samples from GC and peritumoral samples from patients treated at a reference center in the Northern region of Brazil. Among the 22 investigated MMPs, seven genes (MMP2, MMP3, MMP10, MMP12, MMP14, MMP15, and MMP16) were upregulated in cancer, while MMP8 was downregulated. Increased expression of seven of the eight differentially expressed MMPs was found in early stages of the disease compared to Tumor, Node, Metastasis (TNM) stage IV. MMP16 showed higher expression in the diffuse-type gastric adenocarcinoma. An increased expression of MMP10 was observed in the EBV/TCGA group. A significant reduction in survival was noticed in those patients with lower expression of MMP8, MMP12, and MMP14. Transcriptomic correlation analyses demonstrated that differentially expressed MMPs interact with genes likely involved in cell adhesion, ECM organization, and immune response, such as COL1A2, CDH11, KIRREL1, PPP1R14D, CEACAM8, ZNF423, and PRRX1. The enrichment of biological pathways suggests involvement in processes such as ECM organization, collagen and proteoglycan degradation, suggesting that these genes possibly are involved in carcinogenic dynamics, supporting the role of MMPs in tumor ECM reorganization.