Expression of MACC1 and c-Met in human gastric cancer and its clinical significance

Cancer Cell International Expression of MACC1 and c-Met in human gastric cancer and its clinical significance Tiankang Guo 0 Jingyu Yang 2 Jibin Yao 0 Yongbin Zhang 1 Mingxu Da 0 Yaoxing Duan 1 0 Department of Surgical Oncology, Gansu Provincial Hospital , Lanzhou, 730000, PR , China 1 Department of Surgery, Ningxia Medical University , Yinchuan 750004, PR , China 2 Shandong Institute of Parasitic Diseases , Jining 272033, PR , China Background: Recent studies have suggested that the metastasis-associated colon cancer1 (MACC1) gene can promote tumor proliferation, invasion and metastasis through an upregulation of c-Met expression. However, its role in gastric cancer is controversial. Our study investigated expression of MACC1 and c-Met in gastric cancer, as well as correlated this with clinicopathological parameters. Methods: Expressions of MACC1 and c-Met protein in a sample of 98 gastric carcinoma and adjacent nontumorous tissues were detected by immunohistochemistry. Their relationships and correlations with clinicopathological features were analyzed. Results: The positive rates of MACC1 and c-Met protein in primary tumors were 61.22% and 59.18%, respectively. A significant correlation was found between expression of MACC1 and c-Met (P<0.05). Expression of the MACC1 protein in gastric cancer tissue was correlated with lymph node metastasis (2 = 10.555,P = 0.001), peritoneal metastasis (2 = 5.694, P = 0.017), and hepatic metastasis (2 = 4.540,P = 0.033), but not with age, gender, tumor size, location, clinical stage or the distant metastases (P>0.05). Conclusion: The positive rate of MACC1 protein expression was related to the protein expression of c-Met. Both had a correlation with the presence of peritoneal metastasis, lymph node metastasis and hepatic metastasis, all of which contribute to a poor prognosis for gastric cancer patients. Gastric cancer; Metastasis associated with colon cancer1; c-Met; Peritoneal metastasis; Lymph node metastasis; Hepatic metastasis - Introduction Gastric cancer is a common gastrointestinal malignancy. Although the incidence of gastric cancer has declined during the past years, it is still the fourth leading cause of cancer-related death. Gastric cancer is the second most frequent cause of cancer-associated death in malignant tumors that accounts for about 10.4% [1]. An analysis of the global incidence of cancer mortality showed that there are nearly 900,000 new cases and 700,000 cancer deaths in the world. The incidence of gastric cancer is significantly different in different countries and regions. Gastric cancer is the second most frequently diagnosed cause of cancer death in China [2]. Gastric cancer is a multifactorial disease with a complex interplay between genetics and both lifestyle and environmental factors, which consequently results in malignant transformation and progression of gastric cancer. Unfortunately, there has been no specific signature of gastric cancer gene expression reported to allow for patient-tailored therapy strategies. Accordingly, there is great demand to further identify novel oncogenes and clinically applicable molecular targets for the diagnosis and treatment of this disease. Recent observations have suggested that the metastasisassociated colon cancer1 (MACC1) gene can promote tumor proliferation, invasion and metastasis, which is an independent prognostic indicator of recurrence and disease-free survival. The hepatocyte growth factor (HGF)/ mesenchymalepithelial transition factor (c-Met) pathway plays a key role in the carcinogenic pathway [3]. Hepatocyte growth factor (HGF) is a glycoprotein secreted by a variety of mesenchymal or tumor cells [4], which promote migration, invasion, wound healing and survival and suppress apoptosis by c-Met. Met transmits intracellular signals via the mitogen-activated protein kinase (MAPK) and PI3K AKT pathways. MACC1 was reported to be elevated in various cancer tissues, including ovarian cancer [5], hepatocellular carcinoma [6], non-small cell lung cancer [7], and oral squamous cell carcinoma [8]. Recently, there have been reports demonstrating that MACC1 may be involved in the growth of blood vessels, lymphangiogenesis and metastasis of gastric cancer [9-11], but little is known regarding its role in gastric cancer development. MACC1 may be involved in the development of gastric cancer through the HGF/c-Met pathway, or as an independent factor in the gastric process, or through other pathways. MACC1 may become a new molecular marker and target for the diagnosis and treatment of gastric cancer proliferation and metastasis. In the present study, we investigated MACC1 and c-Met expression by immunohistochemistry and real-time polymerase chain reaction (RT-PCR) and analyzed the relationship, as well as correlating it with clinicopathological parameters and their clinical significance. Materials and methods Patients and tumor specimens Ninety-eight cases of gastric cancer tissues and adjacent noncancerous mucosa were collected at Gansu Provincial Hospital from Apr 2006 to Feb 2007. Tissue samples for diagnostic purposes were obtained with the consent of each patient. All tumor specimens and corresponding normal tissues were fixed in 10% buffered formalin, embedded in paraffin, and then made into continuous 4 m tissue sections for immunohistochemical examination. All patients had been histologically diagnosed without preoperative radiotherapy, chemotherapy or other anti-cancer therapy. All of the cases received postoperative adjuvant chemotherapy, and all specimens were pathologically confirmed. The study group consisted of 98 patients, 69 males and 29 females, aged 17 to 79 years, the average age (65.34 13.40) years, and the median age 58 years. The staging of gastric cancer was according to the American Joint Committee on Cancer (ACJJ, 7th edition) (Table 1). Rabbit anti-human MACC1 and c-Met antibodies were purchased from Beijing Biosynthesis Biotechnology Co., Ltd., SP immunohistochemical detection kit. DAB chromogenic kit was purchased from Beijing Zhongshan Golden Bridge Biotechnology Co., Ltd. Immunohistochemistry (IHC) Gastric cancer tissues paraffin sections were placed in citrate buffer (pH 6.0) for antigen retrieval. The negative control antibody was replaced by PBS. The positive controls were lung adenocarcinoma specimens expressing MACC1, and c-Met expression of hepatocellular carcinoma. The procedure was in accordance with the immunohistochemical SP detection kit instructions. The diluted density of rabbit anti-human MACC1 antibody was 1:100 and c-Met antibody was 1:150. MACC1 and cMet protein positive products were mainly localized in the cytoplasm. A small number of nuclear membranes were colored pale-brown with a diffuse distribution. Evaluation of IHC staining Positive results were judged by semi-quantitative points [9]. The staining intensity score was 0 (negative), 1 (weak), 2 (medium), and 3 (strong). The integral of the rate of M (...truncated)