bims-midomi 2026-09-06 papers

PLoS One. 2026 ;21(9): e0350622

Association of MDM2 rs2279744 and rs937282 polymorphisms with breast cancer susceptibility and circulating MDM2 and p53 levels in Bangladeshi women: A case-control study.

Mahim Hassan Chowdhury, Farzana Islam, Adiba Ayesha Khan, Md Ayman Siddique, Nushaiba Binte Hasan, Mahinul Islam Samrat, Mehrin Haque Tanisha, Jarin Tasnim, Samiha Mahjabin, Md Nazmul Islam, Md Aminul Haque.

BACKGROUND: The MDM2-p53 signaling pathway plays a central role in tumor suppression, and genetic variants that disrupt this pathway may influence breast cancer (BC) susceptibility. However, data from South Asian populations, particularly Bangladesh, remain limited.
METHODS: A case-control study was conducted in Bangladeshi women, including BC patients and healthy controls (HCs). Genotyping of MDM2 polymorphisms was performed using PCR-based methods. Circulating MDM2 and p53 protein levels were measured using enzyme-linked immunosorbent assays (ELISA). Associations between genotype, protein levels, BC status, and clinicopathological features were evaluated using appropriate statistical models.
RESULTS: Women carrying the heterozygous TG genotype had a markedly increased risk of BC across additive, dominant, and over-dominant models, whereas the GG genotype showed a protective effect under the recessive model. In contrast, rs937282 did not show a significant association with BC risk. Circulating MDM2 levels were significantly elevated in patients compared with controls and varied by rs2279744 genotype, while circulating p53 levels showed an opposite trend. A strong inverse correlation was observed between serum MDM2 and p53 levels, suggesting a potential association with the MDM2-p53 regulatory pathway. Elevated MDM2 levels were also noted in HER2-positive and triple-positive BC subtypes.
CONCLUSION: Together, these findings suggest that the MDM2 rs2279744 polymorphism is associated with breast cancer susceptibility and genotype-specific differences in circulating MDM2 and p53 levels. However, the absence of functional validation limits direct causal inference.

DOI: https://doi.org/10.1371/journal.pone.0350622

Mol Carcinog. 2026 Aug 31.

E3 Ubiquitin Ligase MDM2 Contributes to Proliferation, Migration/Invasion, Epithelial-Mesenchymal Transition, and Glycolytic Reprogramming in Lung Cancer via Ubiquitinating and Degrading MYH11 Protein.

Yanfeng Fang, Wenting Wu, Miaomiao Wen, Dandan Li, Tongtong Zhang, Zheng Feng.

Lung cancer remains the leading cause of cancer-associated death, and aerobic glycolysis is a key hallmark of cancer. Ubiquitination is a post-translational modification involved in the regulation of lung cancer progression. The aim of this study was to investigate E3 ubiquitin ligase mouse double minute 2 (MDM2) and its ubiquitination on myosin heavy chain 11 (MYH11) in lung cancer progression and glycolytic reprogramming. Expression of MYH11 was analyzed using online databases. MDM2 and MYH11 mRNA and protein detection was performed by qPCR and Western blot. Cell proliferation, migration, and invasion were respectively detected using colony formation assay, wound healing assay, and transwell assay. Glycolysis was evaluated by measuring lactate production and glucose consumption. Epithelial-mesenchymal transition (EMT) and glycolysis-associated proteins were measured using Western blot. Xenograft tumor model was established for in vivo analysis. Co-immunoprecipitation (Co-IP) assay was performed to assess ubiquitination effect of MDM2 on MYH11 and their protein interaction. MYH11 was a down-regulated gene in lung cancer and it negatively correlated with glycolysis. Lung cancer cell proliferation, migration, invasion, EMT, and glycolysis were significantly inhibited following MYH11 overexpression. Tumor growth in vivo was also reduced by MYH11. Mechanistically, MDM2 mediated ubiquitination of MYH11 to induce MYH11 protein degradation and downregulation. Knockdown of MDM2 suppressed the malignant phenotypes of lung cancer cells via enhancing MYH11 protein stability in vitro and in vivo. These results suggest that MDM2 reduces MYH11 expression via ubiquitination-mediated degradation of MYH11 protein, thereby enhancing lung cancer cell proliferation, migration/invasion, EMT and glycolysis, and ultimately promoting tumor progression.

Keywords: epithelial‐mesenchymal transition; glycolysis; lung cancer; mouse double minute 2; myosin heavy chain 11; ubiquitination

DOI: https://doi.org/10.1002/mc.70172

J Adv Res. 2026 Aug 31. pii: S2090-1232(26)00687-9. [Epub ahead of print]

Driver genomic lesions in MDM2, CDK4, and JUN co-opt targetable super-enhancer networks to impose liposarcomagenic core regulatory circuitry.

Ye Chen, Ying Zhang, Long Xie, Xiaorui Fan, Jiyang Liu, Tuan Zea Tan, Zhengming Yang, Pushkar Dakle, Suya Zheng, Nan Li, Chenying Wang, Victor Kwanmin Lee, Lingwen Ding, Qiaoyang Sun, Wen Yi, H Phillip Koeffler, Liang Xu.

INTRODUCTION: Amplification of chromosome 12q13-15 spanning MDM2 and CDK4 genes serves as a molecular diagnostic hallmark of dedifferentiated liposarcoma (DDLPS), an aggressive soft-tissue sarcoma. Epigenetic activation of master transcription factors (RUNX proteins, FOSL2, and MYC) establishes a self-reinforcing oncogenic transcriptional circuitry in DDLPS. Nevertheless, the collaborative interplay between genomic alterations and epigenetic dysregulation in defining DDLPS cell identity remains elusive.
OBJECTIVES: This work aimed to elucidate the primary genetic drivers and mechanistic basis of DDLPS-specific core transcriptional regulatory circuitry.
METHODS: We performed integrative chromatin profiling analysis of DDLPS clinical specimens and cell lines to map cis-regulatory landscapes. Cistromes of MDM2, JUN, and E2F1 were delineated through chromatin immunoprecipitation sequencing in two DDLPS models. Essential driver functions and transcriptional regulatory effects of key regulators were assessed via various genetic manipulation approaches. Synergistic interactions between BET-targeting agents and MDM2/p53 or CDK4 inhibitors were quantified by cell viability assays. In vivo xenograft assays evaluated the oncogenic potential of key regulators and the therapeutic efficacy of novel strategies.
RESULTS: Co-amplification of MDM2, CDK4, and JUN during sarcomagenesis converges with BET protein-dependent chromatin remodeling to fuel feed-forward transcriptional circuits among master transcription factors. Mechanistically, excessively expressed MDM2 stabilizes the core regulatory circuitry by forming chromatin-bound complexes with JUN/FOSL2 at cis-regulatory elements, especially super-enhancers across DDLPS genome. Concurrently, CDK4 maintains expression of E2F1 which further fosters transcriptional output of master transcription factors in DDLPS cells. Leveraging DDLPS-selective overexpression of MDM2 and its E3 ligase activity, targeted degradation of BET proteins by MDM2-recruiting proteolysis targeting chimera selectively disrupted the core regulatory circuitry, suppressing DDLPS growth and exhibiting strong synergy with CDK4 inhibitor.
CONCLUSION: DDLPS-associated genomic lesions collaborate with BET-dependent chromatin regulation to establish disease-sustaining transcriptional circuitry. Our findings also provide a mechanistic rationale for harnessing MDM2's E3 ligase activity to therapeutically degrade oncoproteins in MDM2-amplified malignancies.

Keywords: Core transcriptional regulatory circuitry; Epigenetics; Genomic amplification; PROTAC; Sarcoma; Super-enhancer

DOI: https://doi.org/10.1016/j.jare.2026.08.055

Anticancer Res. 2026 Sep;46(9): 5289-5299

Prominent Myxoid and Collagenous Stromal Patterns in Dedifferentiated Liposarcoma: A Comparative Analysis of Immunophenotypic and Genomic Profiles.

Nam-Kyu Choi, So-Woon Kim, Dong-Hoon Kim, Sung-Im DO, Hidetaka Yamamoto, Kiyong Na.

BACKGROUND/AIM: Dedifferentiated liposarcoma (DDL) is defined by amplification of chromosome 12q13-15 but exhibits substantial morphologic heterogeneity, including variable stromal composition. This study aimed to determine whether prominent stromal patterns in DDL are associated with distinct immunophenotypic and genomic profiles.
PATIENTS AND METHODS: Nineteen surgically resected DDLs were evaluated for histologic features, immunophenotype, and targeted genomic alterations using next-generation sequencing. Associations between stromal pattern, immunohistochemistry, copy number alterations, and clinical outcome were analyzed.
RESULTS: All cases demonstrated MDM2 amplification and strong nuclear MDM2 expression, with frequent co-amplification of CDK4. Beyond canonical 12q alterations, recurrent amplifications were identified, including 1q23 (DDR2), 5p15 (TERT), and 12q13 (STAT6). Notably, DDR2 amplification was significantly enriched in collagenous-dominant DDLs compared with myxoid-dominant tumors. Stromal pattern correlated with immunophenotype, with collagenous-dominant tumors showing frequent SMA expression and absence of CD34, whereas myxoid-dominant tumors more frequently expressed CD34. High mitotic activity and mFNCLCC grade 3, but not stromal pattern, were associated with adverse outcome.
CONCLUSION: Prominent stromal patterns in DDL reflect biologically meaningful subsets associated with distinct immunophenotypic features and secondary genomic alterations. In particular, enrichment of DDR2 amplification in collagenous-dominant DDL suggests a potential link between collagen-associated signaling pathways and stromal morphogenesis in this tumor.

Keywords: Dedifferentiated liposarcoma; NGS; collagenous; myxoid; stroma

DOI: https://doi.org/10.21873/anticanres.18373

Iran Biomed J. 2026 06 24.

Tropolone Derivative JO-122(2) Enhances Temozolomide Efficacy and p53-Mediated Apoptosis in Glioblastoma Xenografts.

Oleg I Kit, Aleksey Yu Maksimov, Igor V Golovinov, Natalia S Kuznetsova, Irina V Kaplieva, Daria V Khodakova, Alexander B Sagakyants, Anastasia V Galina, Anna A Shulga, Sofya V Gurova, Elena S Bondarenko, Eduard E Rostorguev, Yurii A Sayapin, Eugeny A Gusakov.

Background: Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, with limited therapeutic options and poor survival. Resistance to standard temozolomide (TMZ) therapy remains a major challenge, necessitating novel agents. Tropolone derivatives, particularly the synthetic trichlorotropolone JO-122(2), have shown broad preclinical antitumor activity. This study aimed to determine whether JO-122(2), alone or combined with TMZ, can suppress GBM growth in vivo and to define the accompanying changes in the p53/MDM2/Bcl-2 apoptotic axis.
Methods: JO-122(2), as monotherapy or combined with TMZ, was evaluated in a U87 MG GBM xenograft model in BALB/c nude mice (n = 8 per group). Tumor volumes were monitored over 25 days, and tumor growth inhibition (TGI) was calculated. Molecular mechanisms were investigated by RT-qPCR and ELISA, assessing gene expression and protein levels of the apoptotic regulators TP53, MDM2, BAX, BCL2, and CASP9.
Results: JO-122(2) and TMZ monotherapy inhibited tumor growth (TGI = 42.08% and 61.44%, respectively). The combination therapy reduced tumor volume 4.9-fold compared to the vehicle control and achieved a TGI of 79.88% (p = 4.20 × 10⁻⁸ vs. control; p = 1.66 × 10⁻³ vs. TMZ; p = 5.97 × 10⁻⁵ vs. JO-122(2)). It also increased p53, Bax, and caspase-9 protein levels and decreased MDM2 and Bcl-2, with concordant upregulation of TP53 and BAX and downregulation of MDM2 and BCL2 mRNA, indicating modulation of the p53/MDM2/Bcl-2 axis.
Conclusion: JO-122(2) exerts potent antitumor effects in GBM, particularly when combined with TMZ, by promoting mitochondrial apoptosis through the coordinated regulation of p53 and its downstream effectors.

Keywords: Apoptosis; Glioblastoma; Tropolone; p53

DOI: https://doi.org/10.22034/IBJ