Lysyl Oxidase (LOX) Transcriptionally Regulates SNAI2 Expression and TIMP4 Secretion in Human Cancers

Abstract

Purpose: Epithelial-to-mesenchymal transition (EMT) is important in cancer progression and metastasis. We and others have previously reported that lysyl oxidase (LOX) is overexpressed in aggressive cancers, is associated with increased mortality, and regulates EMT. However, the mechanism by which LOX mediates EMT is unknown. In this study, we investigated the effect of LOX on mediators of EMT.Experimental Design: We used chromatin immunoprecipitation and promoter luciferase assays to determine the target gene of LOX. To determine the effects of SNAI2 in vivo, we used our metastatic anaplastic thyroid cancer (ATC) mouse model. To investigate the effects of LOX and SNAI2 on MMPs and TIMPs, protein arrays were used. Primary tumors from patients with metastatic, breast and colon cancer, and tissue array for thyroid cancer were assessed for SNAI2 and TIMP4 expression by immunohistochemistry.Results: We found that LOX knockdown decreases SNAI2 expression in cancer cell lines. Furthermore, knockdown of LOX reduced SNAI2 expression in a metastatic mouse model of thyroid cancer. We also demonstrated that LOX binds and transactivates the SNAI2 promoter. We found a direct correlation in thyroid and breast cancer samples between LOX and SNAI2 expression. To understand how LOX/SNAI2 axis mediates these effects, we performed a comprehensive analysis of MMPs/TIMPs. LOX and SNAI2 depletion reduced TIMP4 secretion. Analysis of SNAI2 and TIMP4 expression showed overexpression of both proteins in aggressive thyroid, colon, and breast tumors.Conclusions: Our findings provide new evidence that LOX regulates SNAI2 expression and that SNAI2-mediated TIMP4 secretion plays a role in cancer progression.

Lysyl oxidase induces epithelial‐mesenchymal transition and predicts intrahepatic metastasis of hepatocellular carcinoma

“…It has been reported that LOX is associated with tumor malignancy, especially with distant metastasis that includes bone metastasis, in several types of cancers such as thyroid, breast, nasopharyngeal, gastric and pancreatic cancers. 23,24,27,[34][35][36][37] With reference to HCC, some reports have shown an association between LOX and angiogenesis markers such as vascular endothelial growth factor (VEGF), but none has revealed an association with EMT or metastasis in HCC. We exhaustively examined the role of LOX in HCC using a large transcriptome matrix, which showed that high LOX expression is closely associated with EMT.…”

“…LOX is a copper‐dependent amine oxidase that catalyzes the final enzymatic step required for cross‐linking of collagen and elastin molecules in the extracellular matrix . In malignant tumors, LOX is involved in the remodeling of cancer stroma, and affects cancer metastasis or accelerates dedifferentiation of cancer cells . High LOX expression is reportedly associated with cancer malignancy and cancer metastasis, and reflects patient prognosis in several types of cancer .…”

“…21 In malignant tumors, LOX is involved in the remodeling of cancer stroma, and affects cancer metastasis or accelerates dedifferentiation of cancer cells. [22][23][24] High LOX expression is reportedly associated with cancer malignancy and cancer metastasis, and reflects patient prognosis in several types of cancer. [9][10][11][12][13][14][25][26][27][28] In the context of HCC, it has been reported that high LOX expression is associated with a marker of tumor angiogenesis, but the association between LOX expression and patient outcome, especially HCC metastasis of IM, is still unclear.…”

Lysyl oxidase activates cancer stromal cells and promotes gastric cancer progression: quantum dot-based identification of biomarkers in cancer stromal cells

“…44,45 Stromal-derived LOX could create a milieu that is suitable for metastastic cancer cells. 34,46 Recently, LOX has been considered as one target to control the metastasis of prostate cancer.…”

A molecular approach combined with American Thyroid Association classification better stratifies recurrence risk of classic histology papillary thyroid cancer

“…25 RET mutations upregulate the biogenesis of miRNAs, 26 and emerging work has identified miR30a as important in maintaining PTC differentiation through the inhibition of lysyl oxidase. 27,28 In addition, pAKT localization has been shown to be dependent on the presence of RET rearrangement. 29 In non-invasive areas of PTC co-expressing RET, pAKT expression was diffuse and cytoplasmic.…”