LRIG3 represses cell motility by inhibiting slug via inactivating ERK signaling in human colorectal cancer

Abstract

Metastasis is responsible for 90% of colorectal cancer (CRC)‐related deaths. In the present study, we identified a novel key regulator of CRC metastasis, leucine‐rich repeats and immunoglobulin‐like domains protein 3 (LRIG3), which was significantly decreased in CRC tissues and cell lines. Downregulation of LRIG3 was attributed to copy number loss and promoter hypermethylation. Low LRIG3 expression was positively correlated with metastatic clinical features and shorter survival time. Functional experiments showed that knockout of LRIG3 markedly enhanced CRC cell migration and invasion ability, whereas reintroduction of LRIG3 exerted the opposite effects. Regarding the mechanism, LRIG3 could facilitate the binding of DUSP6 to ERK1/2, resulting in the dephosphorylation of ERK1/2 and subsequently downregulation of slug, an epithelial‐to‐mesenchymal transition trigger, thereby constraining CRC cell motility. Importantly, LRIG3 expression was strongly negatively correlated with slug or p‐ERK1/2 expression in CRC tissues. Collectively, our data suggest that LRIG3 is a novel suppressor of CRC metastasis, reactivation of LRIG3 may be a promising therapeutic approach for metastatic CRC patients.

Single-cell analyses reveal a continuum of cell state and composition changes in the malignant transformation of polyps to colorectal cancer

“…Therefore, decreased expression of NR3C2 in CRC may be another means to increase expression of WNT target genes and drive proliferation in polyps and CRC. LRIG3, a transmembrane protein recently reported to repress cell motility and metastasis in CRC (Zeng et al, 2020) also gradually decreases in expression across the malignancy continuum (Figure S3D).…”

LRIG3 Suppresses Angiogenesis by Regulating the PI3K/AKT/VEGFA Signaling Pathway in Glioma

“…Moreover, Zeng et al showed that LRIG3 is required for the interaction between Dual-specificity phosphatase 6 (DUSP6) and ERK in colorectal cancer. In the absence of LRIG3, DUSP6 could hardly dephosphorylate ERK, suggesting that LRIG3 has potentially more complex biological functions (10). Recently, Yang et al reported that LRIG2 promotes glioma angiogenesis through the EGFR/VEGFA pathway (30).…”

“…LRIG genes are clinically relevant prognostic indicators in several human cancers and play various roles in tumor cell proliferation, migration, invasion, apoptosis, and chemosensitivity (8,9). LRIG3 was the last gene to be discovered in this family and is frequently downregulated in human cancers (10)(11)(12). In fact, LRIG3 acts as a tumor suppressor in GBM, where it modulates proliferation, migration, and invasion of glioma cells by targeting the EGFR and MET signaling pathways (13,14).…”

The prognostic role of LRIG proteins in endometrial cancer

“…Despite this, the downregulated genes are often deleted in human tumors [17]. At the molecular level, the encoded transmembrane protein LRIG1 acts as a negative regulator of growth factor signaling [18,19]; the LRIG2 protein works as a tumor promotor [20][21][22]; and the LRIG3 protein functions as a tumor suppressor [23,24]. Nowadays, a lot of information is being collected on the role of LRIG proteins in human tumors, and there are published studies on the prognostic role of LRIG proteins in different gynecologic malignancies, such as cervical cancer, vaginal carcinoma, and vulvar squamous cell carcinoma [20,23,[25][26][27][28].…”

“…First, it was previously suggested that LRIG3 overexpression could arrest the cell cycle in the G(0)/G(1) phase, and induce apoptosis in cell lines of glioma, prostate cancer, and bladder cancer [30,31]. It was also shown that LRIG3 could negatively control the ERK pathway, which is known to be often upregulated in human cancer [24,32,33]. LRIG3 was cloned by Guo et al in 2004 [15].…”