Adaptor protein LNK promotes anaplastic thyroid carcinoma cell growth via 14-3-3 ε/γ 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 ε/γ 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-NFκB-Bcl-2/Bcl-xL pathway and that the oncogenic effect of LNK largely depends on 14-3-3 ε/γ 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.

SH2B3, Transcribed by STAT1, Promotes Glioblastoma Progression Through Transducing IL-6/gp130 Signaling to Activate STAT3 Signaling

“…On the other hand, SH2B3 was reported to play paradoxical roles in solid tumor initiation and progression. On the contrary, previous studies show that SH2B3 promotes Jak/STAT signaling in myeloproliferative neoplasms (Oh et al, 2010) and promotes ovarian cancer (Ding et al, 2015), breast cancer (Lv et al, 2020), and anaplastic thyroid carcinoma (Zhong et al, 2020) progression. The biological function of FIGURE 9 | Working model.…”

Role of STAT3 in cancer cell epithelial‑mesenchymal transition (Review)

“…Although SH2B3 is considered to act as a negative regulator in hematological cancer, its role in solid tumors remains controversial. SH2B3 was reported to act as a tumor promoter in ovarian ( 84 ), breast ( 85 ) and anaplastic thyroid cancer ( 86 ) cancer. However, compared with matched adjacent normal tissues, SH2B3 was found to be downregulated in colon cancer, and its overexpression led to a decrease in the invasion rate of colon cancer cells ( 87 ).…”

Modulation of JAK-STAT Signaling by LNK: A Forgotten Oncogenic Pathway in Hormone Receptor-Positive Breast Cancer

“…By studying human melanoma tissue arrays and mRNA expression data from available databases, Ding et al found that LNK is overexpressed in patients with melanoma, and that higher expression of LNK is associated with shorter overall survival [127]. Likewise, elevated expression of LNK was detected in patients with thyroid carcinoma [128]. In glioblastoma patients, elevated expression of LNK predicted worse survival [129].…”

“…Interestingly, functional analysis in cell lines has also shown that LNK-associated activities seem to depend upon cell type. For instance, the induction of LNK overexpression in thyroid carcinoma-derived [128] and glioblastomaderived [129] cell lines resulted in increased cell proliferation and migration, as well as protection against apoptosis. These observations agree with clinical data showing an association between LNK overexpression and poor survival in glioblastoma patients [129].…”