LEM domain containing 1 promotes thyroid cancer cell proliferation and migration by activating the Wnt/β‑catenin signaling pathway and epithelial‑mesenchymal transition

Abstract

Thyroid cancer (TC) is the most common type of endocrine malignancy in humans, and its relative incidence has increased continuously in recent years. However, the primary molecular mechanisms of thyroid tumorigenesis and progression remain unclear. Papillary TC (PTC) is the most common subtype of TC. Recent studies have reported that one of the tumorigenesis and progression mechanisms is driven by genetic alterations that regulate the TC cell signaling pathway. In the present study, RNA sequencing (RNA-seq) was performed on 79 paired PTC and adjacent normal thyroid tissues to further study the molecular mechanisms of TC. Reverse transcription-quantitative PCR was used to detect the expression levels of LEM domain containing 1 (LEMD1) in 47 paired PTC and adjacent normal thyroid tissue samples. Initial analysis revealed that LEMD1 expression was significantly upregulated in TC tissues compared with that in normal tissues. The results of the thyroid RNA-seq datasets from The Cancer Genome Atlas were consistent with the RNA-seq analysis results of the present study. High LEMD1 expression increased the risk of lymph node metastasis in patients with TC. The biological function of LEMD1 on cell proliferation, migration, invasion and apoptosis was investigated in vitro via small interfering RNA and overexpression vector. Gene set enrichment analysis indicated that high LEMD1 expression was associated with epithelial-mesenchymal transition (EMT) and the Wnt/β-catenin signaling pathway. Western blotting revealed that LEMD1 modulated the protein expression levels of E-cadherin, N-cadherin, vimentin, β-catenin and cleaved-caspase 3. In conclusion, the present results indicated that LEMD1 may drive TC cell tumorigenesis and progression by activating the Wnt/β-catenin signaling pathway and EMT.

LEM domain containing 1 (LEMD1) transcriptionally activated by SRY-related high-mobility-group box 4 (SOX4) accelerates the progression of colon cancer by upregulating phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway

“…Previous studies have documented that the emergence of molecular hallmarks is an encouraging advancement for the diagnosis and prognosis of colon cancer and molecular-targeted therapy is pivotal for the treatment of colon cancer [ 35 , 36 ]. The role of LEMD1 has been widely investigated in a variety of human cancers, such as gastric cancer [ 37 ], thyroid cancer [ 19 ], oral squamous cell carcinoma [ 20 , 21 ] and all results implied that LEMD1 may act as a potent oncogene in cancers. What is more, Luo et al have elaborated that LEMD1 involved in competing endogenous RNA mechanism contributes to the development of colorectal cancer [ 38 ].…”

“…LEM domain containing 1 (LEMD1), a novel member of CTAs family, has also been reported to participate in various cellular processes. Take cell proliferation for an example, LEMD1 was demonstrated to exacerbate cell proliferation in gastric cancer and thyroid cancer [ 18 , 19 ]. In addition, high expression of LEMD1 is associated with lymph node metastasis and poor prognosis of oral squamous cell carcinoma, and contributes to tumor cell invasion and endothelial transmigration [ 20 , 21 ].…”

LEM domain containing 1 promotes pancreatic cancer growth and metastasis by p53 and mTORC1 signaling pathway

“…For instance, Li et al elucidated the promotive roles of LEMD1 in gastric cancer cell growth by the activation of PI3K/AKT signaling [ 6 ]. Xu et al reported that LEMD1 facilitated thyroid cancer cell growth and metastasis via epithelial mesenchymal transition and activation of Wnt/β-catenin signaling [ 29 ]. In this study, due to GSEA, LEMD1 was proved as an upstream positive regulator of the mTORC1 signaling pathway by phosphorylation in PC cells.…”

Nuclear Dynamics and Chromatin Structure: Implications for Pancreatic Cancer

“…Most LEM proteins are anchored to membranes via either one (Emerin, LAP2β, LEMD1, ANKLE2) or two (LEMD2, MAN1) transmembrane domains; however, ANKLE1 and LAP2α lack transmembrane domains [21,30,38,39 LEMD1, ANKLE1, and ANKLE2 are less well-characterized and are not localized mainly to the nuclear lamina [38,55]. LEMD1 was identified as a testes-associated gene but has since been found to be overexpressed in a number of malignancies, including colon, thyroid, and prostate cancer, and oral squamous cell carcinoma [56][57][58][59]. One study has expressed epitope-tagged LEMD1 and shown its localization to be apparently extranuclear, possibly associated with the endoplasmic reticulum [39].…”

“…One study has expressed epitope-tagged LEMD1 and shown its localization to be apparently extranuclear, possibly associated with the endoplasmic reticulum [39]. Depletion of LEMD1 in various cancer cell types decreased cell growth, invasiveness, and epithelial-mesenchymal transition [57][58][59]; however, a specific cellular function for LEMD1 has yet to be determined. ANKLE1 is a nonmembrane protein normally located mainly in the cytosol, but able to be actively imported into and exported from the nucleus [38,60].…”