Preoperative Serum Lipids as Novel Predictors of Survival in 3575 Papillary Thyroid Cancer Patients.

PURPOSE: The objective of this study is to investigate the association between preoperative serum lipids levels and papillary thyroid cancer (PTC) patients' outcomes. METHODS: A retrospective cohort study including 3575 PTC patients from year 2012-2016 with follow-ups in our institute were enrolled. Preoperative serum lipids were divided into categorical variables by Receiver-operating curves. Univariable and multivariable cox regression models were developed and independent risk factors were used to construct a nomogram to predict disease-free survival (DFS) rate. RESULTS: Among the 3575 patients, the mean follow-up time was 56.7 months. Comparing with the patients with high level of triglycerides (TAG≥0.605 mmol/L) and high-density lipoprotein (HDL≥0.935 mmol/L), those with low level of TAG (hazard ratio [HR] 2.28 [95% CI, 1.35-3.83]) and HDL (HR 1.64, [1.02-2.62]) had a significantly higher risk of recurrence in PTCs. The 5-year DFS rate of patients with low level of TAG was 94.4%, which was much lower than that in the high level group (97.2%, P＜0.001). While TC (P = 0.13), LDL (P = 0.07) and VLDL (P = 0.15) were not statistically correlated with PTCs' recurrence. The nomogram model showed clinical predictive value with the c-index of 0.80 (95% CI 0.73-0.87) and 0.82 (95% CI 0.73-0.90) for 3- and 4-year DFS in the training cohorts. CONCLUSION: In the present study, we provide initial evidence that low levels of TAG and HDL were independently associated with the recurrence of PTC, indicating that preoperative serum concentrations of lipids are helpful in predicting PTC patients' prognosis in clinical practice.

BRAFV600E restructures cellular lactylation to promote anaplastic thyroid cancer proliferation.

Anaplastic thyroid cancer (ATC) is a rare but fatal cancer with BRAF mutation ranging from 30 to 50%. Histone lysine lactylation represents a novel epigenetic mark that translates cellular metabolic signals into transcriptional regulation. It is not clear whether the Warburg effect can promote the proliferation of ATC with BRAFV600E mutation via metabolite-mediated histone lactylation. Our study aimed at illustrating how BRAFV600E restructures the cellular protein lactylation landscape to boost ATC proliferation, and determining whether blockade of protein lactylation can sensitize mutant ATC to BRAFV600E inhibitors. Western blotting was used to evaluate lactylation status. Aerobic glycolysis was intervened by adding cell-permeable ethyl lactate or using metabolic inhibitors. Chromatin immunoprecipitation and RT-qPCR were applied to analyze the expression of growth-related genes. Different chemical inhibitors were used to inhibit BRAFV600E and other enzymes. ATC cell line-derived xenograft model was employed to examine the efficacy of mono and combinatorial therapies. The results showed that aerobic glycolysis in ATC increased global protein lactylation via improving cellular lactate availability. In particular, lactylation on Histone 4 Lysine 12 residue (H4K12La) activated the expression of multiple genes essential for ATC proliferation. Furthermore, oncogenic BRAFV600E boosted glycolytic flux to restructure the cellular lactylation landscape, leading to H4K12La-driven gene transcription and cell cycle deregulation. Accordingly, the blockade of cellular lactylation machinery synergized with BRAFV600E inhibitor to impair ATC progression both in vitro and in vivo. Our results demonstrated an extra beneficial effect of aerobic glycolysis on ATC, revealing a novel metabolism-epigenetics axis suitable for combinatorial therapy with BRAFV600E inhibition.

Integrative Methylome and Transcriptome Characterization Identifies SERINC2 as a Tumor-Driven Gene for Papillary Thyroid Carcinoma.

Most papillary thyroid carcinomas (PTCs) can be diagnosed preoperatively by routine evaluation, such as thyroid ultrasonography and fine-needle aspiration biopsy. Nevertheless, understanding how to differentiate indolent thyroid tumors from aggressive thyroid cancers remains a challenge, which may cause overtreatment. This study aimed to identify papillary thyroid cancer-specific indicators with whole-genome DNA methylation and gene expression profiles utilizing Infinium Methylation EPIC BeadChip (850k) and RNA arrays. In this paper, we report SERINC2 as a potential tumor-driven indicator in PTC. The up-regulated expression levels of SERINC2 were verified in PTC cell lines via qPCR. Then, cell counting kit 8 (CCK-8), wound healing, and flow cytometric assays were performed to confirm the influence of SERINC2 on proliferation and apoptosis in PTC cell lines after intervention or overexpression. Moreover, the investigation of data from the Cancer Dependency Map (DepMap) provided a potential pathway targeted by SERINC2. The activation of the tryptophan metabolic pathway may reduce the dependency of SERINC2 in thyroid cancers. In conclusion, our results demonstrate the whole-genome DNA methylation and gene expression profiles of papillary thyroid carcinoma, identify SERINC2 as a potential tumor-driven biomarker, and preliminarily verify its function in PTC.