Molecular Carcinogenesis最新文献

Papillary thyroid cancer (PTC) often presents as anatomically distinct foci in bilateral lobes. However, it remains controversial whether these foci arise independently from distinct malignant progenitor cells or result from the dissemination of the primary lesion. Fifteen pairs of bilateral PTC at Stage I were enrolled, and sequencing was performed using a 437-cancer-gene panel (Geneseeq). The entire mitochondrial DNA (mtDNA) was also sequenced and analyzed. The genetic alterations and molecular profiles were comprehensively analyzed and compared between the paired bilateral tumors. Fourty-eight mutations were detected in the nuclear genome, all of which were somatic and heteroplasmic. Among these, BRAF^V600E mutation was predominant (25/30, 83.3%). In mtDNA, three mutations (10963A-C, 13193T-C, 13341 C-G) were identified as novel, seven heteroplasmic mutations were detected including six somatic mutations. Discordant genetic alterations were observed between the paired tumors in 86.7% (13/15) of bilateral PTC cases. Our results reveal that the majority of early-stage bilateral PTCs develop from independent malignant clones harboring different genetic backgrounds, which provides insights into the pathogenesis of bilateral PTCs and supports individualized clinical decision-making.

Tobacco smoke is a major risk factor for esophageal squamous cell carcinoma (ESCC), yet only a subset of smokers develop this disease, implicating gene-smoking interactions in modulating individual susceptibility. Through integrative transcriptomic analyses of normal and tumor samples from smokers and nonsmokers, we identify four smoke-responsive genes (CXCL14, HORMAD1, WFDC5, and MPZ) as potential contributors to ESCC carcinogenesis. Among these, HORMAD1 is markedly upregulated in ESCC cells upon exposure to cigarette smoke condensate (10 µg/mL), benzo[a]pyrene (3 µM), or 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (10 µM), correlating with activation of error-prone nonhomologous end joining (NHEJ) in response to DNA damage. Notably, smokers with higher HORMAD1 expression levels exhibit enhanced NHEJ but impaired homologous recombination (HR), leading to increased genomic instability. Through a two-stage case-control study involving 5151 ESCC cases and 5963 controls, we identify two regulatory variants of HORMAD1, rs11204679 and rs33924488, significantly associated with ESCC risk through a gene-smoking interaction (p_interaction = 0.0027). Both variants confer a protective effect among smokers (OR = 0.80, 95% CI: 0.74-0.87, p = 9.58 × 10^{- 8}) but not in nonsmokers (OR = 0.98, 95% CI: 0.90-1.06, p = 0.5950). Mechanistically, the rs11204679 G > C and rs33924488 GA > G- variants attenuate HOXA6 and SOX15 binding at a distal enhancer, respectively, suppressing HORMAD1 expression via long-range chromatin interactions. These findings establish HORMAD1 as a critical mediator of tobacco-related DNA repair dysregulation and a potential biomarker for ESCC risk stratification and precision prevention.

Ultraviolet A (UVA) radiation induces DNA damage both directly, by forming cyclobutane pyrimidine dimers (CPDs), and indirectly, by generating oxidative stress. Cells rely on nucleotide excision repair (NER) and translesion synthesis (TLS) to tolerate these lesions. Xeroderma pigmentosum variant (XP-V) cells, deficient in DNA polymerase eta (pol eta), exhibit a heightened risk of skin cancer due to impaired TLS. While XP-V patients are considered NER-proficient, our findings challenge this assumption by demonstrating that UVA-induced oxidative stress impaired NER activity, leading to increased C > T transitions at CPD sites. Whole-exome sequencing of UVA-irradiated XP-V cells revealed a substantial rise in mutations, with a distinct C > T signature characteristic of defective CPD repair. Notably, pretreatment with the antioxidant N-acetylcysteine (NAC) mitigated this effect, reducing C > T transitions through enhanced NER function and decreasing C > A transversions via its antioxidant properties. These results redefine the mutagenic landscape of XP-V cells, revealing that oxidatively generated damage to NER proteins-rather than TLS deficiency alone-contributes to their elevated mutation burden. Our findings suggest that antioxidant strategies may partially protect XP-V patients from UVA-driven mutagenesis enhancing the cells' DNA repair capacity, ultimately reducing skin cancer and contributing to better overall health outcomes.

Carfilzomib, a second-generation proteasome inhibitor approved for the treatment of multiple myeloma, is a highly potent and selective inhibitor of the CT-L activity of the i20S proteasome. Several studies have shown that carfilzomib (CFZ) can bypass resistance to bortezomib; however, its impact on squamous cell carcinoma of the head and neck is not well understood. This study aimed to evaluate the anticancer potential of CFZ in head and neck cancer cells (HNSCC) by examining its effects on proliferation, apoptosis, and the underlying mechanisms in both HPV-positive and HPV-negative HNSCC. In Vitro validation of CFZ showed an IC50 that was more than fourfold lower in HPV-negative CAL-27 than other HNSCC cell lines. In addition, CFZ inhibited p-Akt and p-S6 and activated p21, which increased growth inhibition and apoptosis in CAL-27 cells. In mice bearing xenografted HPV-negative CAL-27 cells, we confirmed that CFZ reduced tumor growth. Collectively, the cytotoxic effects induced by CFZ involve cell growth inhibition and apoptosis via the PI3K/AKT/mTOR and p21 signaling pathways. This suggests that CFZ is a novel therapeutic agent that can overcome the existing cisplatin resistance used in the treatment of HPV-negative HNSCC.

Gastric cancer (GC) is a highly prevalent and lethal malignancy. This study aims to investigate the role of Growth Differentiation Factor 15 (GDF15) in regulating ferroptosis through the p62/Keap1/Nrf2 pathway and to elucidate its impact on GC progression. GDF15 levels were assessed via Western blot (WB) analysis in both human gastric mucosal cells and GC cell lines. Cellular viability and growth were evaluated using CCK-8 assays and colony formation experiments. Cell migration and invasion capabilities were assessed using wound healing and Transwell assays. Levels of ROS, MDA, GSH, GPX4, and Fe²⁺ in cells were measured using assay kits. JC-1 method was utilized for evaluating mitochondrial membrane potential. Tumor weight changes were recorded in BALB/c nude mouse models. GDF15 was highly expressed in GC cells, and sh-GDF15 inhibited the growth and metastasis of GC cells, increased the expression of ROS and MDA in cells, promoted cell ferroptosis, and inhibited the p62/Keap1/Nrf2 pathway in cells (p < 0.05). Compared to the sh-GDF15 group, treatment with the Nrf2 activator, NK-252 reduced ROS and MDA levels, suppressed ferroptosis, and enhanced the activation of the p62/Keap1/Nrf2 signaling pathway in GC cells. In GC tissues, the sh-GDF15 group showed reduced tumor volume and weight, elevated Keap1, ROS, and MDA expression, decreased p62 and Nrf2 levels, and increased ferroptosis, which were reversed by the addition of NK-252 (p < 0.05). Conclusively, silencing GDF15 inhibits the p62/Keap1/Nrf2 pathway, promoting ferroptosis and suppressing GC progression.

Retraction: M. Tan, D. Zhang, E. Zhang, D. Xu, Z. Liu, J. Qiu, Y. Fan, and B. Shen, "SENP2 Suppresses Epithelial-Mesenchymal Transition of Bladder Cancer Cells Through deSUMOylation of TGF-βRI," Molecular Carcinogenesis 56, no. 10 (2017): 2332-2341. https://doi.org/10.1002/mc.22687. The above article, published online on 02 June 2017, in Wiley Online Library (wileyonlinelibrary.com), has been retracted by Wiley Periodicals LLC. A third party reported to the journal that image elements in Figure 2E of this article had been duplicated and manipulated from a previously published article by a different group of authors and reporting different experimental conditions (Mani et al. 2007 [https://doi.org/10.1073/pnas.0703900104]). Further investigation by the publisher confirmed this duplication and also detected additional duplications between the T24-Vector panel of Figure 5A and the first panel of Figure 5B, as well as duplication and rotation of image elements in the T24-SENP2 panel of Figure 5A and the third panel of Figure 5B. The authors responded to an inquiry by the publisher and stated that there were no issues of duplication between different articles and that the duplications in Figure 5 may have been caused by errors during image preparation. However, the authors were unable to provide original, unmodified data or images for the experiments reported. The retraction has been agreed to because of the duplication of images from another article, as well as duplication and rotation of images and image elements within the same article, which fundamentally compromises the reported conclusions. The authors have stated their consent to the retraction. The authors disagree with the retraction as they have stated they do not agree that image elements were duplicated in Figure 2E.

The stromal microenvironment of tumors, comprised of diverse stromal cells and extracellular matrix (ECM), is intricately influenced by multiple signaling pathways, metabolic regulation, and the cell cycle, significantly contributing to tumor malignancy and therapy resistance. Posttranslational modifications (PTMs), crucial mechanisms for regulating protein function in organisms, engage in tumor initiation, progression, metastasis, and therapy resistance by modulating stromal cell behavior, stromal signal transduction, ECM deposition, and remodeling within the tumor stromal microenvironment. This article explores the regulatory role of PTMs within the tumor stromal microenvironment and reviews recent advancements in cancer therapy focused on PTMs. Targeting PTMs within the tumor stromal microenvironment shows promising potential as a novel approach and direction in cancer treatment.

Autophagy plays a multifaceted role in tumorigenesis. However, the association between genetic variants in autophagy and gastric cancer susceptibility remains unclear. We evaluated the association between single-nucleotide polymorphisms (SNPs) of autophagy-related genes and gastric cancer risk using a cohort of 1,625 cases and 2,100 controls. Next, transcriptomic data were used to analyze differential gene expression and characterize the tumor immune microenvironment (TME). Single-cell RNA sequencing analysis was performed to investigate cell-type-specific expression profiles. In vitro gain/loss-of-function experiments were conducted to explore the biological roles of TRAF6 in cancer cells. We found that TRAF6 rs5030437 G > A conferred an increased risk of gastric cancer (OR = 1.23, 95% CI: 1.06-1.43, p = 1.28 × 10^-3), particularly in males (OR = 1.24, 95% CI: 1.07-1.44, p = 3.69 × 10^-3) and older individuals (OR = 1.41, 95% CI: 1.18-1.68, p = 1.53 × 10^-4). TRAF6 expression was significantly upregulated in tumor tissues, correlating with poor prognosis in gastric cancer patients. Enrichment analyses implicated TRAF6 in immune response and inflammation signaling, manifested as its characteristic cellular expression distribution and influence on the abundance of specific immune cells. In vitro experiments demonstrated that TRAF6 positively regulated autophagy activity and promoted cell viability, migration, and proliferation of gastric cancer cells, which were reversed by autophagy inhibition. This study elucidated the genetic association of rs5030437 G > A and gastric cancer as well as the impacts of TRAF6 on TME dynamics and cancer biology, which provided novel insights into gastric carcinogenesis and the tumor ecosystem.

MicroRNAs (miRNAs) are small regulatory molecules playing important roles in different physiological and pathological processes, but only several miRNAs were functionally characterized in Merkel cell carcinoma (MCC). We previously identified miR-150-5p as one of the differentially expressed miRNAs between MCC metastases and primary tumors. In the present study, we further investigated the functional role of miR-150-5p in MCC progression. Our results revealed that miR-150-5p suppresses the migratory and invasive properties of MCC cells. We identified RNA N6-methyladenosine (m⁶A) demethylase FTO as a direct target of miR-150-5p. Functionally, we showed that FTO enhances proliferative, migratory and invasive properties of MCC cells, and rescued the antitumor effects induced by miR-150-5p. Mechanistically, we demonstrated that FTO stabilizes CTNNB1 transcripts via its m⁶A demethylation activity. Silencing the m⁶A reader YTHDF2 increased, while its overexpression decreased CTNNB1 mRNA and protein levels. Furthermore, the RNA immunoprecipitation assays demonstrated the interaction between CTNNB1 mRNA and YTHDF2. Together, these results suggest that FTO stabilizes CTNNB1 in an m⁶A-dependent manner. In conclusion, our findings uncover the role of miR-150-5p and its target FTO in MCC progression, suggesting the potential of targeting FTO signaling for MCC therapy.

Cell lines are an essential tool in research, leading to new discoveries involving drug studies, prognosis, treatment outcomes, genomic abnormalities, and cellular pathway deviations. There is an ongoing need for new cell lines in cancer research. Cell lines are often initiated by using tissue explants or dissociating cells onto plastic; this proves ineffective with challenging cell lines. Here we report two improved protocols in establishing stable cell lines. The first takes the more classical approach but is paired with fluorescence-activated cell sorting (FACs). The second protocol involves coculturing with feeder cells, coupled with FACs. We demonstrate the use of these protocols in the establishment of 17 cell lines, including several cancer associated fibroblasts (CAFs) and a human papilloma virus (HPV)- positive HNSCC cell line.