Metastasis-Associated in Colon Cancer 1 Is a Novel Survival-Related Biomarker for Human Patients with Renal Pelvis Carcinoma

et al. (2014) Metastasis-Associated in Colon Cancer 1 Is a Novel Survival-Related Biomarker for Human Patients with Renal Pelvis Carcinoma. PLoS ONE 9(6): e100161. doi:10.1371/journal.pone.0100161 Metastasis-Associated in Colon Cancer 1 Is a Novel Survival-Related Biomarker for Human Patients with Renal Pelvis Carcinoma Hailong Hu 0 Dawei Tian. 0 Tao Chen 0 Ruifa Han 0 Yan Sun 0 Changli Wu 0 William B. Coleman, University of North Carolina School of Medicine, United States of America 0 Department of Urology, Tianjin Institute of Urology, Second Hospital of Tianjin Medical University , Tianjin , China Metastasis-associated in colon cancer 1 (MACC1) has recently been identified as a novel independent prognostic indicator for metastasis occurrence, overall survival and cancer-free survival for patients with colon cancer and other solid tumors. In this study, we investigated the role of MACC1 in the development and progression of renal pelvis carcinoma, a form of upper tract urothelial carcinomas. MACC1 protein has been found in the cytoplasm as well as in the nucleus of the transitional epithelial cells of the normal renal pelvis in immunohistochemical (IHC) assays. Quantitative IHC examinations revealed that MACC1 abnormal abundance in cancerous tissues might represent a biological indicator clinically suggestive of tumor malignancy in the renal pelvis. Furthermore, investigation of the association of MACC1 protein levels with clinicopathological parameters in this study has suggested a correlation of MACC1 expression with tumor-node-metastasis stage and histopathological grade of patients with renal pelvis carcinoma, with elevated MACC1 protein levels frequently associated with higher aggressiveness of the disease. Moreover, both disease-free survival and overall survival for the patients in the high MACC1 expression group were significantly lower than those in the low expression group. Multivariate analysis with a Cox proportional-hazards model suggested that MACC1 is indeed an independent prognostic indicator of overall survival and cancer-free survival for patients with renal pelvis carcinoma. Thus, MACC1 may represent a promising prognostic biomarker candidate, as well as a potential therapeutic target for this disease. - . These authors contributed equally to this work. As a malignant tumor arising from the transitional epithelium (a highly elastic epithelial tissue consisting of multiple layers of epithelial cells that line the inner surface of the urinary organs), renal transitional cell carcinoma, or renal urothelial carcinoma (UC) represents the fourth most common cancer in the world [1]. Occurring in the renal pelvis and ureter, upper tract urothelial carcinoma (UTUC) is a disease primarily affecting people between the ages of 50 and 75. Pathologically, UTUC is usually more invasive than bladder UC (60% vs. 15%) and is frequently associated with higher malignancy [2,3,4]. UTUC at renal pelvis, or renal pelvis carcinoma (RPC) represents approximately 5% to 6% of all renal UCs and are more difficult to diagnose than bladder UC. In fact, the 5-year survival rate of RPC patients is lower than that found in bladder UC as metastasis accounts for about 70% of cancer-specific death in RPC [5]. Notoriously difficult for clinical diagnosis, UTUC represents a tremendous challenge for characterization on radiological imaging, as well as for endoscopic visualization and biopsy. Currently, there are five factors that are the most frequently assessed variables for urothelial carcinoma risk stratification prior to definitive therapy: age, tumor architecture, cytology, biopsy tumor grade, and presence of hydronephrosisand. However, although pathologic predictive factors such as tumor stage, grade, carcinoma in situ, lymphovascular invasion, and lymph node invasion may be more accurate than the other clinical factors to predict disease recurrence and patient survival [6], such information is usually not available before the patient has suffered a significant loss of renal reserve and is less likely to be able to endure aggressive treatments. In the last 5 years, researchers have gained great insight into the biology and clinical behavior of UTUC. Considerable progress has been made in the identification of molecular prognostic indicators for patients with urothelial carcinoma and may increase risk prediction accuracy. Signaling molecules that are related to cellular processes such as angiogenesis, cell death, cell adhesion, and cell proliferation have been investigated extensively as the potential prognostic indicators in the development and progression of the disease, such as p53, EGFR, survivin, Bcl-2, Ki-67, Ecadherin, hypoxia-inducible factor 1a (HIF1a), telomerase mRNA component, matrix metalloproteinases (MMP-2, MMP-9, TIMP1 and TIMP-2), and more (reviewed in [7,8]). Identified in a genome-wide analysis as a differentially expressed gene in human colon cancer tissues and metastases, metastasis-associated in colon cancer 1(MACC1) has been suggested as an independent prognostic indicator of metastasis formation and metastasis-free survival for colon carcinoma patients [9]. Detected in a variety of normal tissues, such as intestine, stomach, pituitary gland, kidney, trachea, pancreas, mammary gland, bone marrow, ovary, lung, heart, liver, and B-lymphoblasts, MACC1 is more abundant in the tissues arising from the endoderm (e.g. intestine and stomach) than the tissues originated from mesoderm (e.g. kidney, heart) or ectoderm (e.g. pituitary and mammary gland). Conceivably, MACC1 might play a role in endoderm-derived organogenesis during embryonic development. Originally discovered in colon cancer, MACC1 overexpression has been demonstrated to promote tumor proliferation, invasion, and metastasis in a wide spectrum of solid tumors including gastrointestinal cancers (e.g. colon cancer [9,10], gastric carcinoma [11]), hepatocellular carcinoma [12,13], osteosarcoma [14], glioma [15,16], lung [17,18,19], esophageal [20], pancreatic [21], ovarian [22], cervical and breast cancer [23] (reviewed in [24]). Furthermore, examination of MACC1 expression levels in tumor tissues of various clinical stages has revealed that the highest MACC1 expression level has been observed more often in malignant tumor tissues of patients, who frequently demonstrate more unfavorable clinicopathological features including enhanced lymphnode metastasis and metachronously developed distant metastases. In other cases, such as in rarely metastatic human glioma, MACC1 gene expression is more dramatically up-regulated in the tissues of higher malignancy, reflecting symptomatic deterioration of the disease [15]. Elevated MACC1 expression has thus been suggested to serve as an independent prognostic indicator for cancer recurrence, potential exacerbation from benign into malignant tumors, or under certain circumstances, the onset of metastasis. In addition, MACC1 has also emerged as a predictive indicator (...truncated)