NNMT/1-MNA Promote Cell-Cycle Progression of Breast Cancer by Targeting UBC12/Cullin-1-Mediated Degradation of P27 Proteins.

Cell cycle dysregulation is a defining feature of breast cancer. Here, 1-methyl-nicotinamide (1-MNA), metabolite of nicotinamide N-methyltransferase(NNMT) is identified, as a novel driver of cell-cycle progression in breast cancer. NNMT, highly expressed in breast cancer tissues, positively correlates with tumor grade, TNM stage, Ki-67 index, and tumor size. Ablation of NNMT expression dramatically suppresses cell proliferation and causes cell-cycle arrest in G0/G1 phase. This phenomenon predominantly stems from the targeted action of 1-MNA, resulting in a specific down-regulation of p27 protein expression. Mechanistically, 1-MNA expedites the degradation of p27 proteins by enhancing cullin-1 neddylation, crucial for the activation of Cullin-1-RING E3 ubiquitin ligase(CRL1)-an E3 ubiquitin ligase targeting p27 proteins.  NNMT/1-MNA specifically up-regulates the expression of UBC12, an E2 NEDD8-conjugating enzyme required for cullin-1 neddylation. 1-MNA showes high binding affinity to UBC12, extending the half-life of UBC12 proteins via preventing their localization to lysosome for degradation. Therefore, 1-MNA is a bioactive metabolite that promotes breast cancer progression by reinforcing neddylation pathway-mediated p27 degradation. The study unveils the link between NNMT enzymatic activity with cell-cycle progression, indicating that 1-MNA may be involved in the remodeling of tumor microenvironment.

NNMT contributes to high metastasis of triple negative breast cancer by enhancing PP2A/MEK/ERK/c-Jun/ABCA1 pathway mediated membrane fluidity.

Elucidating the mechanism for high metastasis capacity of triple negative breast cancers (TNBC) is crucial to improve treatment outcomes of TNBC. We have recently reported that nicotinamide N-methyltransferase (NNMT) is overexpressed in breast cancer, especially in TNBC, and predicts poor survival of patients undergoing chemotherapy. Here, we aimed to determine the function and mechanism of NNMT on metastasis of TNBC. Additionally, analysis of public datasets indicated that NNMT is involved in cholesterol metabolism. In vitro, NNMT overexpression promoted migration and invasion of TNBCs by reducing cholesterol levels in the cytoplasm and cell membrane. Mechanistically, NNMT activated MEK/ERK/c-Jun/ABCA1 pathway by repressing protein phosphatase 2A (PP2A) activity leading to cholesterol efflux and membrane fluidity enhancement, thereby promoting the epithelial-mesenchymal transition (EMT) of TNBCs. In vivo, the metastasis capacity of TNBCs was weakened by targeting NNMT. Collectively, our findings suggest a new molecular mechanism involving NNMT in metastasis and poor survival of TNBC mediated by PP2A and affecting cholesterol metabolism.

Needle tract seeding of papillary thyroid carcinoma after fine-needle capillary biopsy: A case report.

BACKGROUND: Fine-needle biopsy is an accurate and cost-efficient tool for the assessment of thyroid nodules. It includes two primary methods: Fine-needle capillary biopsy (FNCB) and fine-needle aspiration biopsy. Needle tract seeding (NTS) is a rare complication of thyroid fine-needle biopsy mainly caused by fine-needle aspiration biopsy rather than FNCB. Here, we present an extremely rare case of a papillary thyroid carcinoma (PTC) patient with FNCB-derived NTS. CASE SUMMARY: We report a 32-year-old woman with PTC who showed subcutaneous NTS 1 year after FNCB and thyroidectomy. NTS was diagnosed based on clinical manifestations, biochemistry indices, and imaging (computed tomography and ultrasound). Pathological identification of PTC metastases consistent with the puncture path is the gold standard for diagnosis. Surgical resection was the main method used to treat the disease. After surgery, thyroid function tests and ultrasound scans were performed every 3-6 mo. To date, no evidence of tumor recurrence has been observed. CONCLUSION: FNCB is a safe procedure as NTS is rare, and can be easily removed surgically with no recurrence. Accordingly, NTS should not limit the usefulness of FNCB.

The effect of the area proportion of the metastatic lesion within the central metastatic lymph node on response to therapy in papillary thyroid carcinoma.

Lymph node (LN) metastasis has been strongly associated with locoregional recurrence and decreased survival time of patients with papillary thyroid carcinoma (PTC). Although the characteristics of the metastatic LNs (mLN) have been determined, including size, number, micro-metastasis and extra-nodal extension (ENE), further analysis is warranted. The present study introduced a new parameter known as the area proportion of the metastatic lesion within the central mLNs (APmCLN). The objective was to evaluate the impact of the APmCLN on response to therapy in patients with PTC. In total, 355 patients with PTC treated with total thyroidectomy and neck dissection, post-operative radioactive iodine and thyroid-stimulating hormone suppression were retrospectively studied. The patients were classified into two groups: Group A (APmCLN ≤75%) and group B (APmCLN >75%). The association of various clinicopathological characteristics between these two groups was investigated. Univariate and multivariate analyses were used to evaluate risk factors associated with a non-Excellent response to therapy and recurrence-free survival (RFS). The analysis showed that APmCLN >75% was significantly associated with extra-thyroidal extension, clinically apparent nodes (cN1), pathological N1b (pN1b), ENE, greater number and larger size of central mLN and larger size of the central LN metastatic lesion. Furthermore, it was reported that chronic lymphocytic thyroiditis, larger central mLN size and APmCLN >75% were independent risk factors for a non-excellent response to therapy. Finally, it was determined that the rate of excellent response to therapy was significantly higher in pathological N1 (pN1) patients with APmCLN ≤75% (108/144, 75.0%) compared with patients with APmCLN >75% (27/47, 57.4%) (P=0.022). However, there was no significant difference (P=0.247) between patients with APmCLN ≤75% and pN0 (132/164, 80.5%). RFS was 89.4% in patients with pN1-APmCLN >75%, whereas those with pN1-APmCLN ≤75% and pN0 did not experience a relapse. Patients with PTC with APmCLN >75% should be regarded as high-risk and may require more aggressive treatment and careful follow-up.