circPVT1 regulates medullary thyroid cancer growth and metastasis by targeting miR-455-5p to activate CXCL12/CXCR4 signaling.

BACKGROUND: Medullary thyroid cancer (MTC) represents 13.4 % of all thyroid cancers-related deaths. The treatments for MTC are very limited especially for patients with distal metastasis. Therefore, it is critical to understand the mechanisms of MTC to pursue novel therapeutic avenues. Here, we studied the function of circPVT1/miR-455-5p in MTC. METHODS: Human MTC tissues and cell lines were used. qRT-PCR and Western blotting were employed to measure expression levels of miR-455-5p, circPVT1, CXCL12, and epithelial mesenchymal transformation (EMT)-related proteins. Colony formation assay, flow cytometry, transwell assay, and scratch wound healing assay were used to assess the abilities of cell proliferation, apoptosis, migration and invasion, respectively. Dual luciferase assay and RNA immunoprecipitation were employed to validate interactions of circPVT1/miR-455-5p and miR-455-5p/CXCL12. Nude mouse xenograft model was used to evaluate the effects of shcircPVT1 and miR-455-5p mimics on tumor growth and metastasis in vivo. RESULTS: miR-455-5p was reduced in MTC tissues and cells while circPVT1 was elevated. Their levels were correlated with prognosis of MTC. Overexpression of miR-455-5p or sh-circPVT1 suppressed EMT and MTC cell proliferation, migration and invasion. miR-455-5p targeted CXCL12 while circPVT1 sponged miR-455-5p. Knockdown of CXCL12 or CXCL12/CXCR4 signaling inhibitor reversed the effects of circPVT1 overexpression or miR-455-5p inhibitor on EMT and MTC cell proliferation, migration and invasion. Knockdown of circPVT1 or miR-455-5p overexpression repressed MTC tumor growth and lung metastasis in vivo. CONCLUSIONS: miR-455-5p suppresses MTC growth and metastasis by targeting CXCL12/CXCR4 signaling pathway while circPVT1 promotes MTC by sponging miR-455-5p. Our study sheds light on the mechanisms of MTC growth and metastasis.

Prediction of ipsilateral and contralateral central lymph node metastasis in unilateral papillary thyroid carcinoma: a retrospective study.

BACKGROUND: Prophylactic central lymph node dissection (CLND) in patients with papillary thyroid carcinoma (PTC) remains controversial and predictive factors for central lymph node (CLN) metastasis in unilateral PTC cases are not well defined. The aims of this study were to evaluate the rate of ipsilateral and contralateral CLN metastasis and to determine the clinicopathologic factors predictive for ipsilateral and contralateral CLN metastasis in unilateral PTC cases. METHODS: We retrospectively reviewed 218 PTC patients with clinically negative-node neck who have received total thyroidectomy with bilateral CLND. Pearson χ(2) test or Fisher exact test and multivariate analysis were used to evaluate relationships between CLN metastasis and demographic factors such as age, sex and the clinicopathologic factors. RESULTS: Ipsilateral and contralateral CLN metastasis were present in 47.7% (104/218) and 13.3% (29/218), respectively. Multivariate analysis showed that tumor size (>1 cm) (P=0.016; OR, 2.005) and age <45 years old (P=0.031; OR, 1.539) were the predictors of ipsilateral CLN metastasis, and prelaryngeal lymph node (LN) metastasis (P=0.028; OR, 2.970) and ipsilateral CLN metastasis (P<0.001; OR, 15.128) independently predicted contralateral CLN metastasis. CONCLUSIONS: CLN metastasis was common in PTC patients with clinically node-negative neck and the most common pattern of CLN metastasis was ipsilateral CLN metastasis. Prophylactic ipsilateral CLND may be an optional procedure and should be considered for patients with a tumor size >1 cm. Therapeutic bilateral CLND should be considered in patients with a tumor size >1 cm and especially, if there exists prelaryngeal LN or ipsilateral CLN metastasis on frozen section analysis.

[Clinical research strategy for cN0 thyroid papillary carcinoma central lymph node dissection].

OBJECTIVE: To discuss the pattern of central lymph node metastasis of cN0 single thyroid papillary carcinoma and provide clinical evidence-supported proof for central lymph node dissection. METHODS: The performed thyroidectomy and bilateral central lymph node dissection for 150 patients with cN0 single papillary thyroid carcinoma. The bilateral central lymph nodes were divided into 4 parts: the cornu inferius cartilaginis thyroideae region of ipsilateral central area, the lower part of ipsilateral central area, the cornu inferius cartilaginis thyroideae region of contralateral central area, the lower part of contralateral central area on the baseline of 1 cm below the cornu inferius cartilaginis thyroideae. We analyzed the differences and influencing factors of lymph node metastasis in these 4 parts. RESULTS: The lymph node metastasis rate in lower part of ipsilateral central area was the highest (56.7%), followed by the lower part of contralateral central area (28.0%), the cornu inferius cartilaginis thyroideae region of ipsilateral central area (17.3%), and the cornu inferius cartilaginis thyroideae region of contralateral central area (0). In the logistic analysis of multiple factors, invaded thyroid capsule was an independent factor for lymph node metastasis in both the cornu inferius cartilaginis thyroideae region of ipsilateral central area (ß = 0.1835, χ(2) = 0.3102, P < 0.05) and lower part of contralateral area (ß = 0.3166, χ(2) = 1.4640, P < 0.05). The patients' age ≥ 45 years (ß = 0.5737, χ(2) = 6.5923) and invaded thyroid capsule (ß = 0.4258, χ(2) = 3.4735) were independent factors for lower part of ipsilateral central area (both P < 0.05). CONCLUSION: The cornu inferius cartilaginis thyroideae region of contralateral central area of cN0 single PTC patients could not be cleared routinely.

[Lateral neck lymph node metastasis in cN0 papillary thyroid carcinoma].

OBJECTIVE: To study the pattern of lymph node spread in papillary thyroid carcinoma (PTC) with clinically negative node (cN0). METHODS: A total of 106 patients with cN0 PTC who underwent total or subtotal thyroidectomy plus unilateral or bilateral lateral neck dissection (LND, level II-V or level I-V) at West China Hospital of Sichuan University between April 2004 and August 2010 were analyzed retrospectively. RESULTS: The lateral neck lymph node metastasis in cN0 PTC was significantly associated with sex (male, P = 0.007), tumor stage (T3/T4, P = 0.006), tumor size (> 1 cm, P = 0.014) and the number of positive central lymph nodes (≥ 2, P < 0.001), but not with age and multifocal tumor. Level III (47/116, 40.5%) was the most prevalent metastatic site, followed by level IV (41/116, 35.3%), level II (18/116, 15.5%) and level V (2/29, 6.9%). Of the cases with lymph node metastases in level III and IV, 89.8% (79/88) of primary thyroid tumors existed in the lower and middle sites of the thyroid lobes, while in the cases with lymph node metastases in level II, 77.8% (14/18) of primary thyroid tumors in the upper sites of the thyroid lobes, and 83.3% of cases with level II metastases were accompanied with level III metastases. Two cases with level V metastases were accompanied with metastases in levels II, III and IV. CONCLUSIONS: LND should be considered for cN0 PTC in male, with T3/T4 lesions and positive central lymph nodes ≥ 2, and the range of dissection should include level III and IV. Dissection of level II should be considered in cN0 PTC with primary tumor localized in the upper site of the thyroid lobe or with level III metastasis. Dissection of level V should be considered at present of metastases in level II, III, and IV. For cN0 PTC with tumor size < 1 cm, confined to the thyroid and without lymph node metastasis in the central compartment, LND is not recommended.