Nidogen 1 and Nuclear Protein 1: novel targets of ETV5 transcription factor involved in endometrial cancer invasion

Abstract

Endometrial cancer is the most frequent malignancy of the female genital tract in western countries. Our group has previously characterized the upregulation of the transcription factor ETV5 in endometrial cancer with a specific and significant increase in those tumor stages associated with myometrial invasion. We have shown that ETV5 overexpression in Hec1A endometrial cancer cells induces epithelial to mesenchymal transition resulting in the acquisition of migratory and invasive capabilities. In the present work, we have identified Nidogen 1 (NID1) and Nuclear Protein 1 (NUPR1) as direct transcriptional targets of ETV5 in endometrial cancer cells. Inhibition of NID1 and NUPR1 in ETV5 overexpressing cells reduced cell migration and invasion in vitro and reduced tumor growth and dissemination in an orthotopic endometrial cancer model. Importantly, we confirmed a significant increase of NUPR1 and NID1 protein expression in the invasion front of the tumor compared to their paired superficial zone, concomitant to ETV5 overexpression. Altogether, we conclude that NID1 and NUPR1 are novel targets of ETV5 and are actively cooperating with ETV5 at the invasion front of the tumor in the acquisition of an invasive phenotype to jointly drive endometrial cancer invasion.

Nidogen-1 is a novel extracellular ligand for the NKp44 activating receptor

“…66 Another study revealed a possible NID1 involvement in the acquisition of migratory and invasive properties by endometrial cancer cells. 67 It has also been shown that NID1 was present at high levels in the secretome of lung metastases in both breast cancer and melanoma. 68 This study showed that NID1 promoted cancer cell migration, invasion, and metastases in the lung.…”

Identification of Nidogen 1 as a lung metastasis protein through secretome analysis

“…Reminiscent of the role of TGFβ in cancer and metastatic progression, NID1 seems to be a tumor suppressor and metastasis promoter in our breast cancer and melanoma models. However, these functions may be cancer type-dependent, as NID1 promoted tumorigenesis and metastasis of endometrial cancer (Pedrola et al 2015), while loss of expression through promoter methylation in colon and gastric cancers (Ulazzi et al 2007) or increased protein degradation in prostate cancer (Ko et al 2015) correlated with enhanced tumor growth and metastasis. One possible mechanism by which NID1 may decrease tumorigenesis could be its strong binding affinity for perlecan, which can be secreted by quiescent ECs to mute proliferative and invasive phenotypes of lung and breast cancer cells in vitro and reduce their protumorigenic and proinflammatory signaling (Franses et al 2011).…”

“…We first examined its role in cell migration and invasion, processes known to be important during metastasis and previously attributed to NID1 expression in endometrial cancer (Pedrola et al 2015). Indeed, NID1 overexpression in MDA-MB-231 and HTB140 cells significantly increased transwell migration and invasion in modified Boyden chamber assays ( Fig.…”

“…This is in agreement with its known role in facilitating ECM formation (Aumailley et al 1993;Dziadek 1995;Tunggal et al 2003) and cell attachment to a NID1-containing ECM (Dedhar et al 1992;Dong et al 1995;Yi et al 1998). Furthermore, NID1 was shown to enhance cell motility (Pedrola et al 2015) and is elevated in the blood of cancer patients compared with healthy controls Khan et al 2014;Li et al 2015), making it an attractive candidate for experimental assessment in our lung metastasis models.…”

Hepatitis B virus X promotes hepatocellular carcinoma development via nuclear protein 1 pathway

“…3B). NUPR1 is involved in various biological functions such as apoptosis, chemotherapy resistance and endoplasmic-reticulum etc [27] and its knockdown decreases migration capability in endometrial cancer cells [12] and pancreatic cancer cells [28]. Migration data also showed concomitant data that HBx overexpressed cells have more wound healing capacity.…”