LIM‐homeobox gene 2 promotes tumor growth and metastasis by inducing autocrine and paracrine PDGF‐B signaling

Abstract

An epithelial-mesenchymal transition (EMT) is a critical process during embryonic development and the progression of epithelial tumors to metastatic cancers. Gene expression profiling has uncovered the transcription factor LIM homeobox gene 2 (Lhx2) with up-regulated expression during TGFβ-induced EMT in normal and cancerous breast epithelial cells. Loss and gain of function experiments in transgenic mouse models of breast cancer and of insulinoma in vivo and in breast cancer cells in vitro indicate that Lhx2 plays a critical role in primary tumor growth and metastasis. Notably, the transgenic expression of Lhx2 during breast carcinogenesis promotes vessel maturation, primary tumor growth, tumor cell intravasation and metastasis by directly inducing the expression of platelet-derived growth factor (PDGF)-B in tumor cells and by indirectly increasing the expression of PDGF receptor-β (PDGFRβ) on tumor cells and pericytes. Pharmacological inhibition of PDGF-B/PDGFRβ signaling reduces vessel functionality and tumor growth and Lhx2-induced cell migration and cell invasion. The data indicate a dual role of Lhx2 during EMT and tumor progression: by inducing the expression of PDGF-B, Lhx2 provokes an autocrine PDGF-B/PDGFRβ loop required for cell migration, invasion and metastatic dissemination and paracrine PDGF-B/PDGFRβ signaling to support blood vessel functionality and, thus, primary tumor growth.

miR-9 and miR-200 Regulate PDGFRβ-Mediated Endothelial Differentiation of Tumor Cells in Triple-Negative Breast Cancer

“…Moreover, miR-9 levels were higher in TNBC than in luminal and HER2 þ subtypes, in accordance with the negative association with hormonal status; ER can in fact mediate the epigenetic silencing of miR-9 (24), strengthening the preferential expression of this miRNA in more aggressive phenotypes. The protumoral effects of miR-9 (e.g., migration, invasion, EMT) resemble the features mediated by PDGFRb (25,26). We showed indeed that miR-9 itself was able to enhance vasculogenic properties both in vitro and in vivo, resembling the addiction of TNBC to PDGFRb signaling for the generation of vascular lacunae (4).…”

Identification of MicroRNAs Differentially Expressed in Lung Carcinoid Subtypes and Progression

“…ACVR2B, coding for the activin receptor type 2B, has been shown to be overexpressed in nephroblastoma as the result of repression of other microRNAs specifically targeting the gene [30]. LHX2, coding for the LIM homeobox gene 2 transcription factor, has been recently associated with tumor growth and metastasis promotion as well as to epithelial-to-mesenchymal transition in breast cancer cells [31]. Finally, 2 additional genes not included in the most relevant pathways considered above are of interest: KLF12 , which is targeted by all 3 microRNAs, and TRPS1 , which is a target of 2 of these microRNAs.…”

Lhx9 gene expression during early limb development in mice requires the FGF signalling pathway

“…This appears to be due to be a result of functional redundancy with Lhx9 and the paralogue of Lhx2 (Wilson et al, 2008;Tzchori and et al, 2009) as both genes show marked overlap in expressed regions during development. Together, Lhx2 and Lhx9 make up the mammalian Apterous group of LIM-HD transcription factors and both have been implicated in human development and disease (Hou and et al, 2013;Kuzmanov and et al, 2014;Vladimirova and et al, 2009).…”