Impaired thyroid hormone sensitivity increases the risk of papillary thyroid cancer and cervical lymph node metastasis.

BACKGROUND: The association of thyroid hormone sensitivity with papillary thyroid carcinoma (PTC) is unclear. This study investigated the relationship between the thyroid hormone sensitivity indices and the risk of PTC and the influence of thyroid hormone sensitivity on the aggressive clinicopathologic features of PTC. METHODS: This retrospective study recruited 1225 PTC patients and 369 patients with benign nodules undergoing surgery in Zhongshan Hospital in 2020. The thyroid hormone sensitivity indices were thyroid feedback quantile-based index (TFQI), TSH index (TSHI) and thyrotropin thyroxine resistance index (TT4RI). We employed logistic regression models to explore the correlation between the thyroid hormone sensitivity indices and the risk of PTC and its cervical lymph node metastasis (LNM). RESULTS: PTC patients had significantly higher levels of TSH, TFQI, TSHI and TT4RI compared to the patients with benign nodules, but thyroid hormone levels did not differ significantly between the two groups. Logistic regression analysis revealed that the higher levels of TFQI, TSHI, and TT4RI were associated with an increased risk of PTC after adjustment for multiple risk factors (TFQI: OR = 1.92, 95% CI: 1.39-2.65, P < 0.001; TSHI: OR = 2.33, 95% CI:1.67-3.26, P < 0.001; TT4RI: OR = 2.41, 95% CI:1.73-3.36, P < 0.001). In addition, patients with decreased thyroid hormone sensitivity had a higher risk of cervical LNM in multiple logistic regression analysis (TFQI: OR = 1.38, 95% CI:1.03-1.86, P = 0.03; TSHI: OR = 1.37, 95% CI:1.02-1.84, P = 0.04; TT4RI: OR = 1.41, 95% CI:1.05-1.89, P = 0.02). CONCLUSION: Impaired sensitivity to thyroid hormone was associated with an increased risk of PTC, and it is also associated with a higher risk of cervical LNM in PTC patients.

Impaired thyroid hormone sensitivity increases risk of cardiovascular events in patients undergoing coronary angiography.

BACKGROUND: Previous studies found inconsistent results on the relationship between thyroid function and cardiovascular risks. This study aimed to investigate the association of thyroid hormone sensitivity with the risk of major adverse cardiovascular events (MACE) and cardiovascular death in a euthyroid population undergoing coronary angiography. METHODS: This prospective cohort study enrolled 1470 euthyroid participants who underwent coronary angiography between March and November in 2013. The participants were followed up from July to November in 2022. Thyrotroph thyroxine resistance index (TT4RI), TSH index (TSHI) and feedback quantile-based index (TFQI) were calculated to evaluate the sensitivity to thyroid hormone. Kaplan-Meier curve and multivariable Cox proportional hazard model were performed to analyze the association between thyroid hormone sensitivity and risk of MACE and cardiovascular death. RESULTS: Among 1089 participants who completed the follow-up, 342 cases of MACE and 77 cardiovascular deaths were identified during a medium follow-up time of 111 months. In the multivariable Cox proportional hazard model, the higher levels of TFQI (HR =1.41, 95%CI 1.08-1.84; P for trend =0.01), TT4RI (HR =1.40, 95%CI 1.06-1.84; P for trend =0.02) and TSHI (HR =1.61, 95%CI 1.22-2.13; P for trend =0.001) were associated with increased risk of MACE. The higher levels of TFQI (HR =2.21, 95%CI 1.17-4.17; P for trend =0.02) and TSHI (HR =2.05, 95%CI 1.08-3.91; P for trend =0.03) were also associated with increased risk of cardiovascular death. CONCLUSION: Impaired sensitivity to thyroid hormone is associated with higher risks of MACE and cardiovascular death in a euthyroid population undergoing coronary angiography.

TNRC6C Functions as a Tumor Suppressor and Is Frequently Downregulated in Papillary Thyroid Cancer.

Our previous study found that trinucleotide repeat containing adaptor 6C (TNRC6C) may act as a tumor suppressor in papillary thyroid cancer (PTC). In this study, we aimed to confirm the effect of TNRC6C on PTC and investigate the underlying molecular mechanism. The difference of mRNA level of TNRC6C between PTC tissue and noncancerous thyroid tissue and the association of expression level of TNRC6C with clinicopathological features of PTC were analyzed using TCGA data. Immunohistochemical assay was performed to detect the protein expression of TNRC6C in PTC and its adjacent noncancerous tissue. Cell proliferation, migration, invasion, and apoptosis were analyzed after knockdown or overexpression of TNRC6C in BCPAP cells. RNA-sequencing was performed to find the target genes of TNRC6C, and potential targets were validated in BCPAP and TPC1 cells. Our results showed that TNRC6C was downregulated in PTC, and lower expression level of TNRC6C was associated with worse clinicopathological features. Overexpression of TNRC6C significantly inhibited proliferation, migration, and invasion of BCPAP cells and promoted its apoptosis, while knockdown of TNRC6C acted the opposite role. By analyzing RNA-sequencing data and TCGA data, 12 genes (SCD, CRLF1, APCDD1L, CTHRC1, PTPRU, ALDH1A3, VCAN, TNC, ECE1, COL1A1, CAMK2N2, and MMP14) were considered as potential target genes of TNRC6C, and most of them were associated with clinicopathological features of PTC in TCGA. All of them except CAMK2N2 were significantly downregulated after overexpressing TNRC6C. Our study demonstrated that TNRC6C functions as a tumor suppressor in PTC and may serve as a useful therapeutic target and prognostic marker for PTC patients.

Lipoprotein(a) concentration is associated with risk of type 2 diabetes and cardiovascular events in a Chinese population with very high cardiovascular risk.

PURPOSE: Evidences have shown that elevated lipoprotein(a) [Lp(a)] levels were associated with a lower risk of type 2 diabetes, but a higher risk of cardiovascular events in general populations. We aim to demonstrate the effect of Lp(a) concentrations on type 2 diabetes and cardiovascular events in a Chinese population with very high cardiovascular risk. METHODS: Seven hundred ninety-eight participants who underwent coronary angiography between March and November 2013 with normal glucose metabolism were followed up from July to December 2018. RESULTS: Five hundred thirty-five participants completed follow-up, and 395 of them had blood glucose data. Among 395 participants with blood glucose data, a total of 28 incident type 2 diabetes were identified during a median follow-up period of 4.42 years. Compared with the patients in the lowest tertile of Lp(a), the multifactorial adjusted HR for type 2 diabetes was 0.29 in the highest tertile (95% confidence intervals (CI) 0.10-0.89; P for trend = 0.03). Among 535 patients who completed follow-up, a total of 80 cases of major adverse cardiovascular events (MACE) were identified during a median follow-up period of 5.08 years. Compared with the patients in the lowest tertile of Lp(a), the multifactorial adjusted HR for MACE was 1.95 in the highest tertile (95% CI 1.05-3.65; P for trend = 0.03). CONCLUSIONS: Elevated Lp(a) levels were associated with a lower risk of type 2 diabetes, but a higher risk of cardiovascular events in a Chinese population with very high cardiovascular risk.

Identification of gene co-expression modules and hub genes associated with lymph node metastasis of papillary thyroid cancer.

Papillary thyroid cancer (PTC) is the most prevalent histological type among thyroid cancers, and some patients are at a high risk for recurrent disease or even death. Identification for the potential biomarkers of PTC may contribute to early discovery of recurrence and treatment. In The Cancer Genome Atlas (TCGA) database, we obtained the information of RNA sequence data and clinical characteristics of PTC. Weighted gene co-expression network analysis (WGCNA) was performed to construct gene co-expression networks and investigate the relationship between modules and clinical traits. Finally, we constructed 16 co-expression modules in 10,428 genes, and three key modules (darkturquoise, lightyellow, and red) associated with tumor N grade were identified. The results of functional annotation indicated that the darkturquoise module was primarily enriched in the regulation of the extracellular matrix (ECM), collagen metabolism, and cell adhesion, the lightyellow module was primarily enriched in the mitochondrial function regulation and energy synthesis, and the red module was primarily enriched in the process of cell junction, apoptosis, and inflammatory response, suggesting their significant role in the progression of PTC. In addition, the hub genes in the three modules were identified and screened for differentially expressed genes (DEGs). Relapse-free survival analyses found that 11 genes (KCNQ3, MET, FN1, ITGA3, RUNX1, ITGA2, PERP, GCSH, FAAH, NGFRAP1, and HSPA5) may play a pivotal role in PTC relapse. In general, our research revealed the key co-expression modules and identified several prognostic biomarkers, which provides some new insights into the lymph node metastasis of PTC.

Long Non-coding Antisense RNA TNRC6C-AS1 Is Activated in Papillary Thyroid Cancer and Promotes Cancer Progression by Suppressing TNRC6C Expression.

Context: Evidences have shown the important role of long non-coding antisense RNAs in regulating its cognate sense gene in cancer biology. Objective: Investigate the regulatory role of a long non-coding antisense RNA TNRC6C-AS1 on its sense partner TNRC6C, and their effects on the aggressiveness and iodine-uptake ability of papillary thyroid cancer (PTC). Design: TNRC6C-AS1 was identified as the target long non-coding RNA in PTC by using microarray analysis and computational analysis. In vitro gain/loss-of-function experiments were performed to investigate the effects of TNRC6C-AS1 and TNRC6C on proliferation, apoptosis, migration, invasion and iodine-uptake ability of TPC1 cells. Expression levels of TNRC6C-AS1 and TNRC6C of 30 cases of PTC tissues and its adjacent normal thyroid tissues were determined. Results: Downregulation of TNRC6C-AS1 or overexpression of TNRC6C inhibited proliferation, migration and invasion of TPC1 cells, while apoptosis and iodine uptake was promoted in TPC1 cells. Suppression of TNRC6C-AS1 significantly increased the expression of TNRC6C in TPC1 cells. The inhibitory effect of TNRC6C-AS1 knockdown on cell proliferation, migration and invasion was attenuated when the expression of TNRC6C was suppressed simultaneously, indicating TNRC6C is a functional target of TNRC6C-AS1. The expression of TNRC6C-AS1 was significantly higher, while the TNRC6C mRNA and protein were significantly lower in PTC tissues than normal adjacent tissues. There was a significant inverse correlation between TNRC6C-AS1 and TNRC6C mRNA in PTC tissue samples. Conclusions: TNRC6C-AS1 promotes the progression of PTC and inhibits its ability of iodine accumulation by suppressing the expression of TNRC6C. Targeting TNRC6C-AS1 - TNRC6C axis may be a new promising treatment for PTC.