GROα Is Highly Expressed in Adenocarcinoma of the Colon and Down-Regulates Fibulin-1

Abstract

Purpose: The growth-related oncogene a (GROa) is a secreted interleukin-like molecule that interacts with the CXCR2 G-protein^coupled receptor. We found that the mRNA and protein products of GROa are more highly expressed in neoplastic than normal colon epithelium, and we studied potential mechanisms by which GROa may contribute to tumor initiation or growth. Experimental Design: Cell lines that constitutively overexpress GROa were tested for growth rate, focus formation, and tumor formation in a xenograft model. GROa expression was determined by Affymetrix GeneChip (241 microdissected colon samples), real-time PCR (n = 32), and immunohistochemistry. Primary colon cancer samples were also employed to determine copy number changes and loss of heterozygosity related to the GROa and fibulin-1 genes. Results: In cell cultures, GROa transfection transformed NIH 3T3 cells, whereas inhibition of GROa by inhibitory RNA was associated with apoptosis, decreased growth rate, and marked up-regulation of the matrix protein fibulin-1. Forced expression of GROa was associated with decreased expression of fibulin-1. Expression of GROa mRNA was higher in primary adenocarcinomas (n = 132), adenomas (n = 32), and metastases (n = 52) than in normal colon epithelium (P < 0.001). These results were confirmed by real-time PCR and by immunohistochemistry. Samples of primary and metastatic colon cancer showed underexpression of fibulin-1 when compared with normal samples.There were no consistent changes in gene copy number of GROa or fibulin-1, implying a transcriptional basis for these findings. Conclusion: Elevated expression of GROa is frequent in adenocarcinoma of the colon and is associated with down-regulation of the matrix protein fibulin-1 in experimental models and in clinical samples. GROa overexpression abrogates contact inhibition in cell culture models, whereas inhibition of GROa expression is associated with apoptosis. Importantly, coexpression of fibulin-1 with GROa abrogates key aspects of the transformed phenotype, including tumor formation in a murine xenograft model. Targeting GRO proteins may provide new opportunities for treatment of colon cancer.

GROα expression and its prognostic implications in laryngeal squamous cell carcinoma

“…The data are consistent with that reported in a previous study, in which the mRNA expression of GROα was found to be significantly increased in colon adenocarcinoma tissue when compared with that in adjacent normal tissue [27]. We further investigated the expression of GROα protein levels in TMAs prepared from LSCC specimens.…”

“…Multiple studies have since implicated a relationship between the expression of GROα and various human cancers [10,[15][16][17][18]. Recently, it has been reported that GROα plays a critical role in human cancers through several potential signaling pathways, including NF-κB [26], phosphatidylinositol-3-kinase [19] and MEKK1/p38 [27]. CXCR2, the receptor of GROα, interacts with this chemokine with high affinity.…”

Areca nut exposure increases secretion of tumor‐promoting cytokines in gingival fibroblasts that trigger DNA damage in oral keratinocytes

“…For instance, GRO‐α is a potential mediator of cancer invasion in several human cancers such as gastric cancer26 and colon adenocarcinoma 27. IL‐8 is capable of promoting cancer progression by regulating angiogenesis through autocrine and paracrine mechanisms 28, 29.…”

Custom Design of a GeXP Multiplexed Assay Used to Assess Expression Profiles of Inflammatory Gene Targets in Normal Colon, Polyp, and Tumor Tissue

“…A number of these previously have been reported to be increased in gut inflammation and or colon tumors. [13][14][15][16][17] They also have been reported to be involved in angiogenesis 27 and metastasis. 28,29 Notably, Table 1.…”

“…10.001. gut and have been reported to show altered expression in colon tumor tissue. [13][14][15][16][17] Inflammation is widely recognized as a component of cancer, with inflammatory bowel diseases known to lead to increased risk of colon carcinogenesis. 18,19 Hence, gastrointestinal inflammatory signaling pathways and their regulation present key targets for prevention and therapeutic intervention.…”