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Abnormal Expression of Forkhead Box J2 (FOXJ2) Suppresses Migration and Invasion in Extrahepatic Cholangiocarcinoma and Is Associated with Prognosis

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Abnormal Expression of Forkhead Box J2 (FOXJ2) Suppresses Migration and Invasion in Extrahepatic Cholangiocarcinoma and Is Associated with Prognosis INTERNATIONAL JOURNAL OF ONCOLOGY 46: 2449-2458, 2015 Abnormal expression of Forkhead Box J2 (FOXJ2) suppresses migration and invasion in extrahepatic cholangiocarcinoma and is associated with prognosis YONG QIANG1,2*, FEIRAN WANG1*, SUJUAN YAN3, Haitao ZHANG4, LIRONG ZHU1, ZHEN CHEN1, FANG TU5, DONGZHI WANG1, GANG WANG1, WEI WANG1 and ZHONG CHEN1 1Department of Hepatobiliary Surgery, Affiliated Hospital of Nantong University and Research Institute of Hepatobiliary Surgery of Nantong University, Nantong, Jiangsu 226001; Departments of 2General Surgery and 3Gynaecology and Obstetrics, The First People's Hospital of Jingmen, Dongbao District, Jingmen, Hubei 448000; 4Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001; 5Department of Operating Rooms, Shayang People's Hospital, Shayang, Hubei 448200, P.R. China Received February 2, 2015; Accepted March 30, 2015 DOI: 10.3892/ijo.2015.2957 Abstract. Extrahepatic cholangiocarcinoma (CC) is an aggres- samples. Overexpression FOXJ2 expression markedly inhibited sive malignancy with dismal prognosis and characterized cell proliferation, migration and invasion in vitro. FOXJ2 is a by early invasion, metastasis and postoperative recurrence. transcription factor that has been reported to induce epithelial- Therefore, understanding the main molecular mechanisms of mesenchymal transition (EMT). These findings indicated that this malignancy is the key for the development of novel and FOXJ2 gene played a tumor suppressor role in extrahepatic effective therapeutic strategies for extrahepatic CC. Foxj2 is CC, which proposed this gene as a new therapeutic target for a novel forkhead factor. Several FOX family members have extrahepatic CC patients. been reported to play an important role in tumorigenesis and the progression of certain cancers. In this study, real- Introduction time quantitative RT-PCR (qRT-PCR), western blotting, and immunohistochemical staining were used to examine FOXJ2 Cholangiocarcinoma (CC) is a malignant tumor that arises expression in extrahepatic CC tissues and adjacent normal bile from the ductal epithelium of the biliary tree (1). CC accounts duct tissues. The molecular mechanisms of FOXJ2 expression for ~3% of all gastrointestinal malignancies; however, it and its effects on cell proliferation, migration and invasion represents the second most common hepatic malignancy after were also explored by MTT assay, wound healing assay hepatocellular carcinoma (HCC) (2). CC is currently classified and Transwell assay. The relationships between the FOXJ2 as intrahepatic CC and extrahepatic CC, depending on the expression levels, the clinicopathological factors, and patient carcinogenic site. Extrahepatic CCs are further divided into survival were investigated. FOXJ2 mRNA and protein levels hilar (Klatskin tumor) or distal tumors and the incidence of were downregulated in extrahepatic CC tissues compared this cancer has been increasing in recent years (3). Surgical to adjacent normal bile duct tissues. In addition, decreased resection remains the only potentially curative therapeutic FOXJ2 was associated disease progression in extrahepatic CC option, however, as a result of the early invasion and metastasis, more than half of patients present with unresectable disease at diagnosis (4). Although many patients may receive exten- sive surgical resection and adjuvant chemotherapy to improve chance of cure, the therapeutic effect and postoperative Correspondence to: Professor Zhong Chen, Department of Hepato- prognosis are still unsatisfactory, with a 5-year survival rate biliary Surgery, Affiliated Hospital of Nantong University and of 30-42% for hilar CC, and 18-54% for distal CC (5,6). Thus, Research Institute of Hepatobiliary Surgery of Nantong University, discovery of new relevant biomarker to increase specificity or 20 Xisi Road, Nantong, Jiangsu 226001, P.R. China E-mail: [email protected] sensitivity for early diagnosis and to improve the prognosis of extrahepatic CC is important and urgently needed. *Contributed equally Fork-head factors are transcription factors that share an evolutionarily conserved DNA-binding domain, termed the Key words: extrahepatic cholangiocarcinoma, FOXJ2, prognosis, ‘fork-head’ or ‘winged-helix’ domain (7). Most members of the epithelial-mesenchymal transition Fork-head Box (FOX) family have been reported to be widely distributed across several organs and tissues in very different species from yeast to humans and play extraordinarily diverse 2450 Qiang et al: FOXJ2 in extrahepatic cholangiocarcinoma roles that are critical to the organism (8). Nowadays, mounting to the time of patient death or the last follow-up, was used as evidence suggests that FOX family members are important for a measure of prognosis. Postoperative follow-up occurred at a wide spectrum of biological processes, including metabo- our outpatient department and included clinical and labora- lism, development, differentiation, proliferation, apoptosis, tory examinations every 3 months for the first 2 years, every migration, invasion, and longevity (9). Deregulation of FOX 6 months during the third to fifth years until patient death. family genes leads to congenital, diabetes mellitus, or carci- nogenesis (10). Cell culture and transfection. The human extrahepatic CC cell Given their important role in the expression of numerous line QBC939 were purchased from a cell bank at the Chinese genes that affect cell proliferation, differentiation and survival, Academy of Sciences and grown in RPMI-1640 medium FOX family members may represent direct targets, and indirect (Hyclone, Logan, UT, USA) supplemented with 10% fetal effectors of therapeutic intervention. In addition, FOX family calf serum (Gibco, Grand Island, NY, USA). All cell lines members have been shown to be upregulated or downregu- were cultured at 37˚C in a humidified atmosphere of 5% CO2. lated in many cancers. For example, Foxp1 transcription factor Transfection reagent Lipofectamine 2000 was purchased may function as either an oncogene or as a tumor suppressor from Invitrogen (St. Louis, MO, USA). For overexpression depending on the cell types (11-14). FOXA1 gene is ampli- of FOXJ2, the full-length FOXJ2 cDNA was amplified and fied and overexpressed in esophageal and lung cancer (15). cloned into the pEGFP-N-3 expression vector (GeneChem, Furthermore, FOXJ1 was remarkably upregulated in human Shanghai, China). QBC939 cells were then transfected with a HCC specimens (16). Increased expression of FOXM1 protein negative control vector or a FOXJ2 expressing plasmid using was found in variety of human tumors, including HCC (17), Lipofectamine 2000 according to the manufacturer's instruc- intrahepatic CC (18). tions. Foxj2 is a novel forkhead factor, belonging to the FOX family, with a dual DNA binding specificity (19). Some Real-time quantitative PCR. Total RNA was extracted from studies have shown that FoxJ2 is a transcription factor of this tissues lysate using a Trizol kit (Invitrogen, Carlsbad, CA, family that shows a rather broad expression pattern, both in USA), and cDNA was subsequently synthesized from total the adult as well as during embryonic development, but the RNA using an Omniscript RT kit (Qiagen, Valencia, CA, USA) levels of expression vary between organs and, in each organ, according to the manufacturer's instructions. For detecting the not all cells types express the factor (20). Recent study has mRNA level of FOXJ2, quantitative real-time RT-PCR was reported that upregulation of FOXJ2 might inhibit of cell conducted on the Mastercycler ep realplex (Eppendorf 2S, migration and invasion of breast cancer (21). However, the Hamburg, Germany). A 25-µl reaction mixture contained 1 µl role of FOXJ2 in EHCC has not been explored thus far. In of cDNA from samples, 12.5 µl of 2X Fast EvaGreen™qPCR this study, we surveyed the expression of FOXJ2 in human Master Mix, 1 µl primers (10 mM), and 10.5 µl of RNase/ patient samples. To explore its associated molecular mecha- DNase-free water. PCR procedures: incubation at 96˚C for nisms in extrahepatic CC cells, we examined the effect of 2 min, 40 cycles at 96˚C for 15 sec and 60˚C for 1 min. The targeted overexpression of FOXJ2 gene on cell proliferation, Ct value was defined as the cycle number at which the fluores- migration and invasion in vitro. These studies will be useful cence intensity reached a certain threshold where amplification in identifying potential candidates for targeted therapeutic of each target gene was within the linear region of the reaction intervention of extrahepatic CC. amplification curves. Relative expression level for each target gene was normalized by the Ct value of GAPDH (internal Materials and methods control) using the 2-∆∆Ct relative quantification method. The sequences of the primers for FOXJ2 were: FOXJ2 forward: Patients and clinical samples. We included a total of 63 5'-TATGGTAGGGCATGAGGACAAC-3'; FOXJ2 reverse: paraffin-embedded extrahepatic CC and matched paracancer 5'-GCAAACAATTAAAGGAGGACAAAC-3'. The glyceral- normal bile duct tissue samples from patients who underwent dehyde-3' phosphate dehydrogenase (GAPDH) gene served as surgical treatment at Affiliated Hospital of Nantong University an internal control. during the period from January 2005 to January 2009. The patients or their legal guardian provided written informed Western blot analysis. Since January 2013, fresh surgical spec- consent to the surgical procedures and gave permission to use imens after surgical removal were collected
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