BACKGROUND
Dysregulated lipid metabolism and chemoresistance are key drivers of breast cancer progression. Lectin, mannose-binding 2 (LMAN2) is frequently overexpressed in human breast tumors and functions as an oncogenic driver. However, whether LMAN2 contributes to chemoresistance remains unknown.
METHODS
We integrated multi-omics data from 1,085 primary tumors and matched normal tissues (from GEPIA and UALCAN) with functional studies in breast cancer cell lines and a doxorubicin (ADM)-treated nude mouse xenograft model. LMAN2 expression was modulated via siRNA/shRNA-mediated silencing or lentivirus-driven overexpression. Cellular phenotypes-including proliferation, migration, apoptosis, and response to ADM were systematically assessed. RNA-sequencing, untargeted lipidomics, and rescue experiments identified stearoyl-CoA desaturase (SCD) as a critical downstream effector. IC50 shifts and epistasis analysis further validated the role of the LMAN2/SCD axis in chemoresistance.
RESULTS
LMAN2 mRNA was elevated across all molecular subtypes (luminal > HER2 > triple-negative) and predicted poorer overall survival (P = 5 × 10-4) and progression-free survival (P = 0.018). Silencing LMAN2 reduced clonogenicity by ~ 45% and migration by 37-63%, whereas overexpression increased cell viability by 1.4-1.7-fold and doubled motility. Knockdown of LMAN2 decreased the ADM IC50 by 4-5 fold, abolished macroscopic colony formation, and elevated apoptosis rates from 15 to 18% to 39-41%; these effects were reversed upon LMAN2 overexpression. In vivo, shLMAN2 combined with ADM reduced tumor volume and weight by 72% and 75%, respectively, compared to ADM alone (P < 0.001). Mechanistically, LMAN2 loss downregulated genes involved in "cholesterol homeostasis" and reduced total cellular cholesterol by 24%. SCD emerged as the most significantly downregulated enzyme and fully rescued the phenotypic and chemoresistance effects resulting from LMAN2 modulation. Epistasis experiments confirmed that LMAN2-mediated chemoresistance strictly depends on SCD function.
CONCLUSIONS
LMAN2 is a robust prognostic biomarker that promotes breast tumor growth and anthracycline resistance by enabling SCD-dependent lipid desaturation. Therapeutic targeting of the LMAN2/SCD axis represents a promising strategy to overcome chemoresistance in breast cancer.
Changjiao Yan, Fengqiang Cui, Chutuo Liu et al.· Breast Cancer Research· 0 citations
Abstract Background Thyroid cancer incidence is rising worldwide, yet comprehensive longitudinal data linking contemporary demographic, pathological, and surgical trends to recurrence risk remain scarce. Methods A retrospective analysis was performed on 9504 thyroid cancer patients from 2008 to 2023. Based on the year of treatment, patients were categorized into 3 groups for comparative assessment. Demographic features, clinical pathological characteristics, surgical approaches, and prognostic outcomes were evaluated. Results Over the 16-year period, the annual number of new thyroid cancer cases demonstrated a consistent upward trend, with a growing proportion detected through routine health screenings. The male-to-female ratio was 1:2.76, with a gradual increase in male patients. The peak age at diagnosis remained between 30 and 60 years, while the proportion of juvenile patients declined steadily. Papillary thyroid carcinoma constituted the predominant histologic type. Surgical management shifted toward more conservative approaches. Although tumor size decreased over time, the incidence of multifocal lesions and the BRAF V600E mutation rate rose. Lymph node metastasis rates also increased, particularly in patients with central region metastases and metastases in ≤5 lymph nodes. Multivariate analysis identified age, tumor size, and number of metastatic lymph nodes as independent risk factors for recurrence in papillary thyroid carcinoma. Patients older than 55 years, those with larger lesions, or those with more lymph node metastases exhibited a significantly elevated recurrence risk. Conclusion Although thyroid cancers are being detected at earlier stages and smaller sizes, the burdens of molecular, multifocal, and lymph node disease are increasing. Age, tumor size, and nodal metastatic load constitute robust independent predictors of recurrence in papillary thyroid carcinoma, informing risk-adapted surveillance and surgical strategies.
Sijin Guo, Yang Wang, Changjiao Yan et al.· Journal of the Endocrine Soc...· 0 citations
BACKGROUND
m5C modification plays a vital role in the progression of human cancers, including breast cancer (BC), but the function of NOP2/Sun RNA methyltransferase 2 (NSUN2), an RNA m5C modification enzyme, remains largely unclear.
METHODS
qRT-PCR, western blot and IHC assays were carried out to determine the expression of NSUN2, poly (ADP-ribose) polymerase 1 (PARP9) and Y box binding protein 1 (YBX1). EdU, flow cytometry, transwell, tube formation and sphere formation assays were conducted to evaluate cell proliferation, apoptosis, invasion, angiogenesis and stemness, respectively. ELISA was performed to examine the concentrations of inflammatory factors. RIP and pull-down assays were used to verify the interaction between NSUN2/YBX1 and PARP9. Murine xenograft model was constructed to explore the functions of NSUN2 and PARP9 in tumor growth in vivo.
RESULTS
PARP9 silencing suppressed the proliferation, invasion, angiogenesis, stemness and immune escape, and promoted apoptosis in BC cells in vitro. Mechanically, NSUN2 functioned as an m5C writer that catalyzed m5C modification of PARP9 mRNA, while YBX1 acted as an m5C reader that recognized the modified transcript and enhanced its stability, thereby elevating PARP9 expression in BC cells. YBX1 could elevate PARP9 expression in BC cells. Moreover, NSUN2 knockdown restrained the malignant behaviors of BC cells, with PARP9 overexpression restored the effects. In addition, NSUN2 knockdown blocked tumorigenesis in vivo by regulating PARP9 expression.
CONCLUSION
NSUN2-mediated m5C modification stabilizes PARP9 mRNA and is associated with enhanced BC progression and immune escape. The results broadened our understanding of the pathogenic mechanism of BC.
Xin Li, Changjiao Yan, Jun Yi et al.· Cell Division· 0 citations
