HIF-1α regulates the cell viability in radioiodine-resistant papillary thyroid carcinoma cells induced by hypoxia through PKM2/NF-κB signaling pathway.

The curative treatment options for papillary thyroid cancer (PTC) encompass surgical intervention, radioactive iodine administration, and chemotherapy. However, the challenges of radioiodine (RAI) resistance, metastasis, and chemotherapy resistance remain inadequately addressed. The objective of this study was to investigate the protective role of hypoxia-inducible factor-1α (HIF-1α) in 131 I-resistant cells and a xenograft model under hypoxic conditions, as well as to explore potential mechanisms. The effects of HIF-1α on 131 I-resistant BCPAP and TPC-1 cells, as well as the xenograft model, were assessed in this study. Cell viability, migration, invasion, and apoptosis rates were measured using Cell Counting Kit-8, wound-healing, Transwell, and flow cytometry assays. Additionally, the expressions of Ki67, matrix metalloproteinase-9 (MMP-9), and pyruvate kinase M2 (PKM2) were examined using immunofluorescence or immunohistochemistry assays. Sodium iodide symporter and PKM2/NF-κBp65 relative protein levels were detected by western blot analysis. The findings of our study indicate that siHIF-1α effectively inhibits cell proliferation, cell migration, and invasion in 131 I-resistant cells under hypoxic conditions. Additionally, the treatment of siHIF-1α leads to alterations in the relative protein levels of Ki67, MMP-9, PKM2, and PKM2/NF-κBp65, both in vivo and in vitro. Notably, the effects of siHIF-1α are modified when DASA-58, an activator of PKM2, is administered. These results collectively demonstrate that siHIF-1α reduces cell viability in PTC cells and rat models, while also mediating the nuclear factor-κB (NF-κB)/PKM2 signaling pathway. Our findings provide a new rationale for further academic and clinical research on RAI-resistant PTC.

Mutations Affecting Genes in the Proximal T-Cell Receptor Signaling Pathway in Peripheral T-Cell Lymphoma.

Peripheral T-cell lymphoma (PTCL) comprises a heterogeneous group of mature T-cell malignancies. Recurrent activating mutations and fusions in genes related to the proximal TCR signaling pathway have been identified in preclinical and clinical studies. This review summarizes the genetic alterations affecting proximal TCR signaling identified from different subgroups of PTCL and the functional impact on TCR signaling and downstream pathways. These genetic abnormalities include mostly missense mutations, occasional indels, and gene fusions involving CD28, CARD11, the GTPase RHOA, the guanine nucleotide exchange factor VAV1, and kinases including FYN, ITK, PLCG1, PKCB, and PI3K subunits. Most of these aberrations are activating mutations that can potentially be targeted by inhibitors, some of which are being tested in clinical trials that are briefly outlined in this review. Finally, we focus on the molecular pathology of recently identified subgroups of PTCL-NOS and highlight the unique genetic profiles associated with PTCL-GATA3.

Correlation of thyroid stimulating hormone receptor mRNA expression levels in peripheral blood with undesirable clinicopathological features in papillary thyroid carcinoma patients.

To determine the extent to which thyroid stimulating hormone receptor (TSHR) mRNA in peripheral blood (PB) has diagnostic value for papillary thyroid carcinoma (PTC). We obtained pre- and postoperative PB samples from 104 thyroid disease patients and collected 11 healthy volunteers' PB samples twice apiece at different times. We used reverse transcription polymerase chain reaction (RT-PCR) to quantify TSHR mRNA expression levels in the samples. T-test and chi-square test were used to compare quantitative data and rates. The mean preoperative PB TSHR mRNA expression level of the PTC patients was significantly higher than that of the healthy volunteers. However, on the postoperative day 1, PB TSHR mRNA level of PTC patients significantly decreased but not for healthy controls. Preoperative PB TSHR mRNA expression levels were significantly associated with patient age, capsular invasion status, lymph node metastasis status, and BRAFV600E mutation status (P < 0.05) but not gender, tumor size, number of cancer foci, or Hashimoto thyroiditis status. Preoperative assessment of the PB TSHR mRNA expression level combined with ultrasonography of the thyroid had better accuracy in the diagnosis of PTC than either method alone did. Moreover, TSHR mRNA expression significantly affected recurrence of PTC patients. Our findings suggest that PB TSHR mRNA expression level is a promising novel biomarker for the early detection, diagnosis, and treatment of PTC. It may serve as a noninvasive means of PTC detection and a prognostic biomarker of residual tumor and help guide further treatment.

Patterns and clinical significance of cervical lymph node metastasis in papillary thyroid cancer patients with Delphian lymph node metastasis.

Although the roles of Delphian lymph node (DLN) metastasis in papillary thyroid cancer (PTC) have been previously reported, there are still limited data on correlations of clinicopathologic factors with DLN metastasis and unique patterns of cervical node subsite metastasis in PTC patients with DLN metastasis. We retrospectively reviewed medical records of 320 patients with a diagnosis of PTC who underwent primary surgery. Clinicopathologic features and DLN metastasis patterns were analyzed for predicting extensive cervical lymph node metastasis. Both univariate and multivariate Cox regression analyses were used to identify independent factors for cervical lymph node metastasis. DLN metastasis was significantly associated with multifocality, tumor size > 1 cm, extrathyroid extension, BRAFV600E mutation, central neck node metastasis (CNNM), and lateral neck nodes metastases. Patients with DLN metastasis had more lymph node metastases in the central compartment. CNNM number and tumor size > 1 cm were independent risk factors for DLN metastasis. DLN metastasis was highly predictive of lateral lymph node metastasis with moderate sensitivity and high specificity. DLN metastasis is associated with several poor prognostic factors, including extensive cervical lymph node metastasis, and can serve as a predictor of advanced PTC. The presence of DLN metastasis should prompt surgeons to perform an aggressive surgery approach.

BRAF-Activated Long Noncoding RNA Modulates Papillary Thyroid Carcinoma Cell Proliferation through Regulating Thyroid Stimulating Hormone Receptor.

PURPOSE: The importance of long noncoding RNAs (lncRNAs) in tumorigenesis has recently been demonstrated. However, the role of lncRNAs in development of thyroid cancer remains largely unknown. MATERIALS AND METHODS: Using quantitative reverse transcription polymerase chain reaction, expression of three lncRNAs, including BRAF-activated long noncoding RNA (BANCR), papillary thyroid cancer susceptibility candidate 3 (PTCSC3), and noncoding RNA associated with mitogen-activated protein kinase pathway and growth arrest (NAMA), was investigated in the current study. RESULTS: Of the three lncRNAs (BANCR, PTCSC3, and NAMA), expression of BANCR was significantly up-regulated while PTCSC3 and NAMA were significantly down-regulated in papillary thyroid carcinoma (PTC) compared to that in normal tissue. BANCR-knockdown in a PTC-derived cell line (IHH-4) resulted in significant suppression of thyroid stimulating hormone receptor (TSHR). BANCR-knockdown also led to inhibition of cell growth and cell cycle arrest at G0/G1 phase through down-regulation of cyclin D1. In addition, BANCR was enriched by polycomb enhancer of zeste homolog 2 (EZH2), and silencing BANCR led to decreased chromatin recruitment of EZH2, which resulted significantly reduced expression of TSHR. CONCLUSION: These findings indicate that BANCR may contribute to the tumorigenesis of PTC through regulation of cyclin D1 and TSHR.

Efficacy and toxicity of adding cetuximab to chemotherapy in the treatment of metastatic colorectal cancer: a meta-analysis from 12 randomized controlled trials.

Cetuxiamb, a monoclonal antibody against epidermal growth factor receptor (EGFR), has been used in combination with chemotherapy for patients with metastatic colorectal cancer (mCRC). However, the efficacy of combined therapies of cetuximab and different chemotherapy regimens remains controversial. Therefore, we conducted a meta-analysis to evaluate the efficacy and toxicity of adding cetuximab to oxaliplatin-based or irinotecan-based chemotherapeutic regimens for the treatment of patients with mCRC with wild-type/mutated KRAS tumors. Randomized controlled trials (RCTs), published in Pubmed and Embase were systematically reviewed to assess the survival benefits and toxicity profile mCRC patients treated with cetuximab plus chemotherapy. Outcomes included overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and toxicities. Results were expressed as the hazard ratio (HR) with 95 % confidence intervals (CI). Pooled estimates were generated by using a fixed-effects model or a randomized-effects model, depending on the heterogeneity among studies. A total of 12 trials involving 6,297 patients met the inclusion criteria and were included in this meta-analysis. All patients were administered oxaliplatin-based or irinotecan-based chemotherapy with or without cetuximab. Pooled results showed that the addition of cetuximab did not significantly improve the OS (HR = 0.99, 95 % CI = 0.89-1.09; Z = 0.28, P = 0.78) or PFS (HR = 0.94, 95 % CI = 0.81-1.10; Z = 0.76, P = 0.49), but did improve ORR (RR = 1.34, 95 % CI = 1.08-1.65; Z = 2.72, P = 0.00), when compared with chemotherapy alone. Subgroup analysis showed the highest PFS benefit in patients with wild-type KRAS tumors (HR = 0.80, 95 % CI = 0.65-0.99; Z = 2.1, P = 0.04) or wild-type KRAS/BRAF tumors (HR = 0.64, 95 % CI = 0.52-0.79; Z = 4.15, P = 0.00). When combined with cetuximab, irinotecan-based chemotherapy was significantly associated with prolonged PFS (HR = 0.79, 95 % CI = 0.66-0.96; Z = 2.36, P = 0.02) for all patients with differing gene-status. The incidence of grade 3/4 adverse events, including skin toxicity, diarrhea, hypertension, anorexia, and mucositis/stomatitis, was slightly higher in the combined therapy group than in the chemotherapy-only group. Based on the current evidence, the addition of cetuximab to chemotherapy significantly improves the PFS in patients with wild-type KRAS or wild-type KRAS/BRAF tumors as well as the ORR in all patients. In addition, irinotecan-based combination therapy showed a beneficial effect on the PFS in all patients. These findings confirm the use of cetuximab in combination with chemotherapy for the treatment of patients with mCRC with wild-type KRAS tumors. Further multi-center RCTs are needed to indentify these findings.