Molecular Carcinogenesis最新文献

Gastrointestinal stromal tumor (GIST) frequently develops resistance to imatinib (IM). This study identifies AOC3 downregulation as a critical contributor to IM resistance. Analyzing clinical samples and IM-sensitive/resistant GIST cell lines, we found AOC3 significantly decreased in resistant states. Functionally, AOC3 knockdown promoted IM resistance, enhanced glycolytic activity, and increased lactate production. Mechanistically, AOC3 loss attenuated ubiquitin-mediated degradation of HK2, stabilizing this glycolytic enzyme and boosting lactate generation. Subsequent histone lactylation, notably at H3K18, enriched at the Myc promoter and stimulated its transcription. Crucially, HK2 overexpression reversed AOC3's suppressive effects on glycolysis, lactylation, Myc expression, and IM resistance. In vivo xenograft models confirmed these findings. We conclude that AOC3 acts as a tumor suppressor by promoting HK2 degradation; its loss triggers a HK2/glycolysis/lactylation/Myc axis driving IM resistance, positioning AOC3 as a promising prognostic biomarker and therapeutic target in GIST.

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.

Hypoxic and nutrient-deprived conditions are characteristics of the solid tumors' microenvironment (TME), where hypoxia-inducible factor (HIF) and autophagy serve as the central modulators in cancer cells. Herein, we synthesize decades of research regarding HIF and autophagy in cancer, highlighting their regulatory roles in modulating progression, such as HIF-1α-BNIP3/BNIP3L-Beclin-1 complex signaling and HIF-mTOR-ULK1 axis. Given the paucity of comprehensive syntheses regarding this intricate interplay, we systematically deconstruct recent findings to map the molecular landscape connecting HIF-1 to autophagic flux and cell death. Specifically, we explore the metabolic bridges linking HIF and autophagy, including glycolysis and reactive oxygen species (ROS). Furthermore, by refining the content of dual-target molecules, we propose strategies for co-targeting HIF and autophagy, aiming to catalyze the development of novel therapeutic interventions.

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.

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.

Pancreatic cancer (PC) endangers patients' lives and health, and the current diagnosis and treatment situation is not optimistic. Bile acids level was reported to be involved in PC progression, but how they regulate PC progression at the molecular level remains unclear. There is an urgent need to conduct in-depth research. Clinical samples from 58 PC patients and PC cells, including PANC-1 cells and CFAC-1 cells, served as the main research objects. RT-qPCR, IHC, and western blot were used to detect the levels of related molecules. Bile acids, lactate, triglycerides, and cholesterol levels were measured by commercial kits and the lipid levels were evaluated by Oil Red O assay. CCK-8, EdU, and Transwell assays were employed to detect malignant features of PC cells. In PC clinical samples, fatty acid-binding protein 6 (FABP6) expression and endogenous bile acid levels were abnormally elevated. Besides, FABP6 overexpression could accelerate tumor growth and metastasis and facilitated lipid metabolism reprogramming in PC mice. In addition, in PC cells, FABP6 overexpression promoted cellular lipid metabolism by enhancing intracellular bile acid transport, which promoted the malignant characteristics of PC cells. As expected, FABP6 silencing achieved opposite results. Moreover, FABP6 overexpression affected lipid metabolism reprogramming and promoted PC cell malignant features by strengthening intracellular bile acid transport to activate NR1H2/3. FABP6 overexpression promoted lipid metabolism reprogramming by enhancing intracellular bile acid transport to activate NR1H2/3, thereby accelerating PC progression. These findings offered new insights into PC molecular mechanisms and potential therapeutic targets.

Chemotherapy continues to be the standard of care for metastatic malignancies, such as triple-negative breast cancer (TNBC). Although the treatment strategy increases survival rates marginally, it frequently leads to the development of resistant disease and side effects. It is imperative to develop an alternate chemotherapy formulation with better efficacy and lesser adverse effects in TNBC patients. Cell viability and cholesterol level were measured using spectrophotometer and fluorometric assays. The 4T1 syngeneic BALB/c female mice were used as an in vivo metastatic TNBC model. Simvastatin (Sim) and Metformin (Met) were administered in combination (3.5-7.0 and 175-350 μg/g body weight, respectively) and alone (Sim 7.0 μg/g/day, or Met 350 μg/g/day) orally over an 8-week period, and the standard Anticancer drug docetaxel (Doc) was administered at a dose of 24 μg/g body weight through IP injection every 3 weeks. Phosphorylation levels of protein and histopathology of tumors were studied by immunoblot and H & E staining methods, respectively. We report that the viability of TNBC cells is significantly and synergistically reduced by Sim and Met co-treatment, with negligible adverse effects on normal breast cell line. Sim Met combination down regulates phosphorylation at specific sites of AKT (Ser-473/Thr-308) and AMPKα (Ser-485/491) and up regulates ACC phosphorylation (Ser-79), which in turn minimizes the cellular cholesterol synthesis in the TNBC model. Further study demonstrated that the combination significantly reduced tumor formation effectively than docetaxel. Study confirmed that the combination of Sim and Met is a promising chemotherapeutic approach for metastatic TNBC.

Metastasis remains the primary determinant of poor prognosis in nasopharyngeal carcinoma (NPC). While dysregulated ubiquitination drives cancer progression, the functional contributions of deubiquitinating enzymes (DUBs) to NPC dissemination are poorly defined. Here, we investigated USP2, a DUB implicated in oncogenesis, as a potential regulator of NPC migration and invasion. In our study, bioinformatics analysis of the GEO data set GSE200792 identified USP2 as a metastasis-associated gene with elevated m⁶A methylation and mRNA levels in metastatic NPC. Validation employed qPCR, Western blot, and immunohistochemistry in clinical samples and NPC cell lines. Functional assays included CCK-8, flow cytometry, Transwell, wound healing, and mechanistic studies such as cyclohexane chase, co-immunoprecipitation, ubiquitination assays were performed under USP2 knockdown/overexpression and NF-κB inhibition. Our results showed that USP2 was significantly upregulated in metastatic NPC tissues and cell lines. USP2 knockdown suppressed proliferation, migration, and invasion, induced apoptosis, and attenuated NF-κB activation by reducing nuclear p65 and TRAF2/MMP2 expression. Conversely, USP2 overexpression enhanced malignancy, which was reversed by NF-κB inhibition. Critically, USP2 directly bound MMP2, extended its protein half-life, and reduced K48-linked polyubiquitination. In conclusion, USP2 drives NPC migration and invasion by activating TRAF2-dependent NF-κB signaling and directly mediating K48-linked deubiquitination of MMP2, dually enhancing MMP2 expression. Targeting the USP2-MMP2 axis may offer a novel therapeutic strategy to impede NPC dissemination, addressing an unmet clinical need in advanced disease.

Prostate cancer (PCa) is one of the most common genitourinary malignancies in men worldwide. As a 5-methylcytosine (m5C) methyltransferase, NSUN2 has been implicated in regulating PCa progression. This study aimed to investigate the role of NSUN2 in PCa and elucidate its underlying mechanisms. The biological behaviors of PCa cells were assessed using Cell Counting Kit-8, EdU incorporation, and Transwell assays. The expression levels of relevant RNAs were determined via quantitative real-time PCR. The interaction between NSUN2 and YES proto-oncogene 1 (YES1) was examined through methylated RNA immunoprecipitation (MeRIP), RNA immunoprecipitation (RIP), and dual-luciferase reporter assays. Results showed that NSUN2 was elevated in PCa, and its downregulation suppressed cell viability, proliferation, migration, and invasion. Mechanistically, NSUN2 interacted with YES1 and stabilized its mRNA by promoting m5C modification on YES1. The oncogenic role of NSUN2 was further confirmed in xenograft models in vivo. In conclusion, our study demonstrated that NSUN2 facilitated malignant proliferation and migration of PCa cells by enhancing YES1 mRNA stability via m5C modification. These findings suggested that both NSUN2 and YES1 may serve as potential therapeutic targets for PCa, offering new strategies for treatment.

M2-like tumor-associated macrophages (TAMs) exert immunosuppressive and protumorigenic functions in hepatocellular carcinoma (HCC). In this study, we explored the function and mechanism of Type IIA topoisomerase (TOP2A) in TAM recruitment and M2 polarization in the HCC microenvironment. The IGF2BP3-TOP2A relationship was confirmed by RIP, MeRIP, luciferase, and mRNA stability assays. Coculture experiments using a transwell system were performed to analyze the impact on the migration, CD206⁺ cell population, and M2-related marker expression in THP-1-differentiated macrophages (THP-1-M0). Xenograft models were constructed to evaluate TOP2A's role in tumor growth. Expression analysis was performed by quantitative PCR (qPCR), immunoblotting, and immunohistochemical staining. Increased TOP2A expression was associated with advanced tumor stage and worse outcomes in HCC. IGF2BP3 was upregulated and positively correlated with TOP2A expression in HCC samples. TOP2A depletion reduced THP-1-M0 migration and M2 polarization in vitro and attenuated xenograft growth by suppressing TAM infiltration and M2 polarization in vivo. Mechanistically, IGF2BP3 recognized METTL3-catalyzed m6A sites to increase the stability and expression of TOP2A mRNA. TOP2A re-expression abolished IGF2BP3 knockdown-driven suppression of THP-1-M0 migration and M2 polarization. Moreover, TOP2A depletion decreased CCL2 production and YAP1 activation. CCL2 reconstruction or the Hippo pathway inhibitor XMU-MP-1 reversed TOP2A knockdown-driven suppression of THP-1-M0 migration and M2 polarization. Our findings identify the IGF2BP3/TOP2A axis as a master regulator of TAM recruitment and polarization in HCC via IGF2BP3-m6A-dependent TOP2A stabilization to facilitate YAP1-mediated CCL2 upregulation, providing novel strategies to overcome immunosuppression and combat HCC.