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Adaptor protein LNK promotes anaplastic thyroid carcinoma cell growth via 14-3-3 ?/? binding.

ABSTRACT: Background:Rapid progression contributes to treatment failure in anaplastic thyroid carcinoma (ATC) patients. In a preliminary study, we demonstrated that some hematopoietic factors may be involved in the progression of ATC. The adaptor protein LNK, which is a negative regulator of hematopoietic cytokine signalling, has been studied extensively in malignant hematopoietic cells. However, there are few studies on LNK in solid tumours. Methods:Real-time PCR, immunohistochemistry (IHC) and western blot analysis of LNK were performed on ATC cells, differentiated thyroid cancer (DTC) cells and normal thyroid cells. In vitro assays (including pull-down, liquid chromatography-mass spectrometry (LC-MS), co-IP, MTT and colony formation) were performed to validate the effect of LNK on ATC progression and elucidate the molecular mechanisms. Results:Compared with DTC cells and normal thyroid cells, ATC cells exhibit overexpression of LNK. In addition, LNK overexpression results in increased proliferation of ATC cells. Conversely, LNK knockdown significantly suppresses ATC cell proliferation. LC-MS identified the 14-3-3 ?/? protein as a LNK binding partner. Finally, the results indicate that LNK overexpression significantly enhances the anti-apoptotic ability of ATC cells via the Akt-NF?B-Bcl-2/Bcl-xL pathway and that the oncogenic effect of LNK largely depends on 14-3-3 ?/? binding. Conclusions:The present study elucidated the important role of LNK in the growth of ATC opposite to its behaviour in the hematopoietic system and indicates that LNK is a potential target for the treatment of ATC.

SUBMITTER: Zhong ZM

PROVIDER: S-EPMC6953139 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Adaptor protein LNK promotes anaplastic thyroid carcinoma cell growth via 14-3-3 ε/γ binding.

Zhong Zhao-Ming ZM Chen Xue X Qi Xiao X Wang Xue-Min XM Li Chun-Yan CY Qin Ru-Jia RJ Wang Shi-Qi SQ Liang Jin J Zeng Mu-Sheng MS Sun Chuan-Zheng CZ

Cancer cell international 20200109

<h4>Background</h4>Rapid progression contributes to treatment failure in anaplastic thyroid carcinoma (ATC) patients. In a preliminary study, we demonstrated that some hematopoietic factors may be involved in the progression of ATC. The adaptor protein LNK, which is a negative regulator of hematopoietic cytokine signalling, has been studied extensively in malignant hematopoietic cells. However, there are few studies on LNK in solid tumours.<h4>Methods</h4>Real-time PCR, immunohistochemistry (IHC ...[more]

PMID: 31938019

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Project description:Anaplastic thyroid cancer (ATC) is one of the deadliest human cancers and it is less than 2% of thyroid carcinomas (TCs). The standard treatment of ATC includes surgical debulking, accelerated hyperfractionated external beam radiation therapy (EBRT), and chemotherapy, in particular with cisplatin or doxorubicin, achieving about 10 months of median survival. Since ATC is a rare and aggressive tumor, it is still challenging to predict the patient clinical therapy responsiveness. Several genetic mutations have been described in ATC, involved in different molecular pathways linked to tumor progression, and novel therapies acting on these molecular pathways have been investigated, to improve the quality of life in these patients. Here we review the new targeted therapy of ATC. We report interesting results obtained with molecules targeting different pathways: angiogenesis (vandetanib, combretastatin, sorafenib, lenvatinib, sunitinib, CLM94, CLM3, etc.); EGFR (gefitinib, docetaxel); BRAF (dabrafenib/trametinib, vemurafenib); PPARγ agonists (rosiglitazone, pioglitazone, efatutazone); PD-1 and PD-L1 (pembrolizumab); TERT. To escape resistance to monotherapies, the evaluation of combination strategies with radiotherapy, chemotherapy, or targeted drugs is ongoing. The results of clinical trials with dabrafenib and trametinib led to the approval from FDA of this combination for patients with BRAF V600E mutated ATC with locally advanced, unresectable, or metastatic ATC. The anti-PD-L1 antibody immunotherapy, alone or combined with a BRAF inhibitor, has been shown also promising in the treatment of ATC. Furthermore, to increase the therapeutic success and not to use ineffective or even harmful treatments, a real tailored therapy should be pursued, and this can be achieved thanks to the new available genomic analysis methods and to the possibility to test in vitro novel treatments directly in primary cells from each ATC patient. Exploring new treatment strategies is mandatory to improve the survival of these patients, guaranteeing a good quality of life.

Project description:Anaplastic thyroid carcinoma (ATC) is an extremely malignant type of endocrine cancer frequently accompanied by extrathyroidal extension or metastasis through mechanisms that remain elusive. We screened for the CREB3 transcription-factor family in a large cohort, consisting of four microarray datasets. This revealed that CREB3L1 was specifically up regulated in ATC tissues and negatively associated with overall survival of patients with thyroid cancer. Consistently, high expression of CREB3L1 was negatively correlated with progression-free survival in an independent cohort. CREB3L1 knockdown dramatically attenuated invasion of ATC cells, whereas overexpression of CREB3L1 facilitated the invasion of papillary thyroid carcinoma (PTC) cells. Loss of CREB3L1 inhibited metastasis and tumor growth of ATC xenografts in zebrafish and nude mouse model. Single-cell RNA-sequencing analysis revealed that CREB3L1 expression gradually increased during the neoplastic progression of a thyroid follicular epithelial cell to an ATC cell, accompanied by the activation of the extracellular matrix (ECM) signaling. CREB3L1 knockdown significantly decreased the expression of collagen subtypes in ATC cells and the fibrillar collagen in xenografts. Due to the loss of CREB3L1, ATC cells were unable to activate alpha-smooth muscle actin (α-SMA)-positive cancer-associated fibroblasts (CAFs). After CREB3L1 knockdown, the presence of CAFs inhibited the growth of ATC spheroids and the metastasis of ATC cells. Further cytokine array screening showed that ATC cells activated α-SMA-positive CAFs through CREB3L1-mediated IL-1α production. Moreover, KPNA2 mediated the nuclear translocation of CREB3L1, thus allowing it to activate downstream ECM signaling. These results demonstrate that CREB3L1 maintains the CAF-like property of ATC cells by activating the ECM signaling, which remodels the tumor stromal microenvironment and drives the malignancy of ATC. Graphical Abstract Supplementary Information The online version contains supplementary material available at 10.1186/s12943-022-01658-x.

Project description:BackgroundAnaplastic thyroid cancer (ATC) is one of the most lethal forms of cancer with a high mortality rate. Current guidelines support surgery for resectable ATC followed by external beam radiation therapy (EBRT) with or without chemotherapy. Treatment for those who are unresectable is palliative. Our goal was to examine first-line therapies as well as the role of genomic profiling in an effort better understand how to approach ATC.MethodsThis is a retrospective study of ATC patients who were seen at our institution from January 2013 to October 2015. Median overall survival (OS) and time to treatment failure (TTF) were calculated by the Kaplan-Meier method.ResultsFifty-four patients were included. Median age at diagnosis was 63 years and 29/54 (54%) were women. The majority had stage IVC disease at diagnosis (50%), followed by IVB (32%), and IVA (18%). Approximately 93% had somatic gene testing. Initial treatment was surgery in 23 patients, EBRT with or without radiosensitizing chemotherapy in 29 patients, and systemic chemotherapy in 2 patients. Nineteen patients had all three treatment modalities. For the entire cohort, median OS was 11.9 months with 39% survival at 1 year and median TTF was 3.8 months. The majority of patients (74%) developed new distant metastasis or progression of existing metastatic disease. Patients who received trimodal therapy consisting of surgery, EBRT, and chemotherapy had a median OS of 22.1 months versus 6.5 months in those who received dual therapy with EBRT and chemotherapy (p = 0.0008). The TTF was the same in the two groups (7.0 and 6.5 months, respectively). Men were three times more likely to die from ATC than women (p = 0.0024). No differences in OS or TTF were noted based on tumor size (5 cm cutoff), age (60 years cutoff), or presence of any mutation. There was a trend toward shorter TTF in patients with somatic mutations in TP53.ConclusionPatients with ATC amenable to aggressive tri-modal therapy demonstrate improved survival. The short TTF, due primarily to distant metastatic disease, highlights the potential opportunity for improved outcomes with earlier initiation of systemic therapy including adjuvant or neoadjuvant therapy.

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Adaptor protein LNK promotes anaplastic thyroid carcinoma cell growth via 14-3-3 ?/? binding.

Publications

Adaptor protein LNK promotes anaplastic thyroid carcinoma cell growth via 14-3-3 ε/γ binding.

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