BackgroundPhosphatase of regenerating liver-3 (PRL-3) plays a causative role in tumor metastasis, but the underlying mechanisms are not well understood. In our previous study, we observed that PRL-3 could decrease tyrosine phosphorylation of integrin β1 and enhance activation of ERK1/2 in HEK293 cells. Herein we aim to explore the association of PRL-3 with integrin β1 signaling and its functional implications in motility, invasion, and metastasis of colon cancer cell LoVo.MethodsTranswell chamber assay and nude mouse model were used to study motility and invasion, and metastsis of LoVo colon cancer cells, respectively. Knockdown of integrin β1 by siRNA or lentivirus were detected with Western blot and RT-PCR. The effect of PRL-3 on integrin β1, ERK1/2, and MMPs that mediate motility, invasion, and metastasis were measured by Western blot, immunofluorencence, co-immunoprecipitation and zymographic assays.ResultsWe demonstrated that PRL-3 associated with integrin β1 and its expression was positively correlated with ERK1/2 phosphorylation in colon cancer tissues. Depletion of integrin β1 with siRNA, not only abrogated the activation of ERK1/2 stimulated by PRL-3, but also abolished PRL-3-induced motility and invasion of LoVo cells in vitro. Similarly, inhibition of ERK1/2 phosphorylation with U0126 or MMP activity with GM6001 also impaired PRL-3-induced invasion. In addition, PRL-3 promoted gelatinolytic activity of MMP2, and this stimulation correlated with decreased TIMP2 expression. Moreover, PRL-3-stimulated lung metastasis of LoVo cells in a nude mouse model was inhibited when integrin β1 expression was interfered with shRNA.ConclusionOur results suggest that PRL-3's roles in motility, invasion, and metastasis in colon cancer are critically controlled by the integrin β1-ERK1/2-MMP2 signaling.

High Mycoplasma infection in gastric cancer tissues suggests a possible association between Mycoplasma infection and tumorigenesis. By using human gastric cancer cells AGS and mouse melanoma cells B16F10 stably expressing p37, the major immunogen of Mycoplasma hyorhinis, we found that p37 enhanced cell motility, migration, and invasion in vitro. With experimental metastasis model in C57BL/6 mice, p37 adenovirus-infected B16F10 cells formed more metastasis lesions in the lung. Furthermore, p37 promoted the phosphorylation of epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase and the activity of matrix metalloproteinase-2 (MMP-2). Inhibitor of MMPs significantly blocked p37-induced EGFR but has little effect on extracellular signal-regulated kinase phosphorylation, whereas the p37-induced MMP-2 activation was only partially suppressed by inhibitor of MEK1/2 or by inhibitor of EGFR. However, all these inhibitors significantly reduced the p37-induced invasiveness of AGS cells. These results suggest that p37 may stimulate invasion by increasing the activity of MMP-2, thereby inducing EGFR phosphorylation and contributing to tumor metastasis on M. hyorhinis infection. p37 and its regulated molecules could be the potential targets for cancer therapy. [Mol Cancer Ther 2008;7(3):530 -7]

Synuclein c (SNCG), previously identified as a breast cancer-specific gene (BCSG1), is highly expressed in breast carcinomas but not in normal epithelium. SNCG regulates many pathways in growth and progression of breast cancer. To determine if SNCG is a biomarker for clinical prognosis of breast cancer, we generated a panel of murine monoclonal antibodies (mAbs) against human SNCG and correlated SNCG protein expression in 358 clinical breast cancer specimens with clinical outcome. A panel of 14 mAbs was characterized by ELISA, immunoprecipitation (IP), Western blot, immunocytochemistry and immunohistochemistry. SNCG protein expression was determined in 438 clinical breast specimens by immunohistochemical analysis using mAb 5C5. Expression of SNCG was strongly correlated with the stage, lymph node involvement, metastasis, tumor size and Her-2 status, but its expression was not associated with ER and PR expression status. While 71.4% of advanced breast cancers were positive for SNCG expression, only 26.8% of Stage I/II breast cancers were positive for SNCG expression and 5.2% of benign hyperplasia expressed SNCG. SNCG protein was not detectable in normal tissue adjacent to breast cancer. After a median follow-up of 64 months, patients with an SNCG-positive tumor had a significantly shorter disease-free survival and overall survival and a high probability of death compared no expression of SNCG. Multivariate analysis demonstrated that SNCG was a strong independent prognostic variable. SNCG is a new unfavorable prognostic marker for breast cancer progression and a potential target for breast cancer treatment. ' 2007 Wiley-Liss, Inc.Key words: synuclein gamma; breast cancer; prognosis; chaperone protein Synucleins are a family of small proteins consisting of 3 known members, synuclein a (SNCA), synuclein b (SNCB) and synuclein g (SNCG). 1 Although they are homologous, each synuclein is encoded by a different gene on chromosomes 4q21.3-q22 (SNCA), 5q35 (SNCB) and 10q23 (SNCG). 2 Synucleins have been specifically implicated in neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). 2 Mutations in SNCA are genetically linked to several independent familial cases of PD. 3 More importantly, wild type of SNCA is the major component of Lewy bodies in sporadic PD and in a subtype of AD. 4,5 SNCA peptide known as nonamyloid component of plaques has been implicated in amyloidogenesis in AD. 6,7 SNCB has also been recognized to play a role in the pathogenesis of PD and Lewy bodies. 8 While SNCG shares 54 and 56% amino acid sequence identity with SNCA and SNCB, respectively, interestingly SNCG is not clearly involved in neurodegenerative diseases. SNCG was first identified as a breast cancer-specific gene BCSG1 by differential cDNA sequencing approach. 9 Several studies have demonstrated that SNCG mRNA is abnormally expressed in a high percentage of advanced and metastatic breast tumors but not in normal or benign breast tissues. 9-12 Overexpression of SNCG also correlated with ovarian cancer p...

N-α-Acetyltransferase 10 protein (Naa10p, also called arrest-defective 1), the catalytic subunit of N-acetyltransferase A, is a critical regulator of cell death and proliferation. Naa10p is also shown to regulate cancer metastasis by inhibiting cell motility; however, its role in cancer metastasis is not fully understood. In this study, we found that high expression of Naa10p is positively correlated with the survival of patients with breast cancer, whereas negatively correlated with lymph node metastasis. Naa10p inhibits breast cancer cell migration and invasion in vitro and decreases the xenograft growth and metastasis in nude mice. Microarray screening revealed that Naa10p downregulates inhibitors of differentiation 1 (ID1) expression. Naa10p binds to signal transducer and activator of transcription 5a (STAT5a) and decreases STAT5a-stimulated ID1 expression in an acetyltransferase-independent manner. Moreover, Naa10p antagonizes Janus kinase 2-STAT5a signaling by lowering p65-activated interleukin-1β expression. Our results demonstrate a novel mechanism through which Naa10p inhibits the metastasis of breast cancer cells by targeting STAT5a.

Laparoscopic surgery is an acceptable alternative to open surgery in colorectal cancer treatment. However, in gastric cancer, there is not much scientific evidence. Here, we proposed a prospective randomized clinical trial to evaluate the radicalness and safety of laparoscopic D2 dissection for gastric cancer. From October 2010 to September 2012, 300 patients with gastric cancer were randomized to undergo either laparoscopy-assisted gastrectomy (LAG) or conventional open gastrectomy (OG) with D2 dissection. Clinicopathological parameters, recovery and complications were compared between these two groups. Thirty cases were excluded because of refusing to be involved in the trial, having peritoneal seeding metastasis or LAG conversed to OG, and finally 270 cases were analyzed (128 in LAG and 142 in OG). No significant differences were observed in gender, age, body mass index, stages and types of radical resection [radical proximal gastrectomy (PG + D2), radical distal gastrectomy (DG + D2) and radical total gastrectomy (TG + D2)] (P > 0.05). The number of harvested lymph nodes (HLNs) was similar (29.3 ± 11.8 in LAG vs. 30.1 ± 11.4 in OG, P = 0.574). And in the same type of radical resection, no significant difference was found in the number of HLNs between the two groups (PG + D2, P = 0.770; DG + D2, P = 0.500; TG + D2, P = 0.993). The morbidity of the LAG group (21.8 %) was also comparable to the OG group (19.0 %, P = 0.560). However, the LAG group had significantly less blood loss and faster recovery, and a longer operation time (P < 0.05). Laparoscopic D2 dissection is feasible, safe and capable of fulfilling oncologic criteria for the treatment of gastric cancer.

N-α-Acetyltransferase 10 protein (Naa10p/ARD1), the catalytic subunit of N-acetyltransferase A, catalyzes both N-α-acetylation and ε-acetylation, as well as autoacetylation. Naa10p is involved in controlling cell proliferation, apoptosis, autophagy and neuronal development. Our group and others had reported prognostic value of Naa10p expression in various types of cancer. Despite the efforts to elucidate the biological function of Naa10p, it remains controversial regarding its roles in tumor development. Herein, we report that depletion of Naa10p inhibited the growth of xenograft tumors in nude mice. Microarray analysis identified MCL1 gene as one of targets downstream of Naa10p. Naa10p positively regulated MCL1 expression, as exogenous Naa10p promoted MCL1 expression, whereas Naa10p silencing decreased MCL1 expression. Ablation of Naa10p sensitized cancer cells to stimuli-induced apoptosis, and the anti-apoptotic function of Naa10p was, at least in part, mediated by MCL1. Mechanistically, we found a physical interaction between Naa10p and RelA/p65. Transcriptional activation of the MCL1 gene required the recruitment of Naa10p-RelA/p65 complex to the p65-binding site of MCL1 promoter region. We also demonstrated a positive correlation between MCL1 and Naa10p messenger RNA levels in both colon cancer and lung cancer tissues. These results indicate that Naa10p inhibits apoptosis through Naa10p-RelA/p65-dependent MCL1 transcriptional activation.

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Phosphatase of regenerating liver-3 (PRL-3) is overexpressed in several human cancers and associated with tumor progression, invasion and metastasis. However, the correlation between PRL-3 expression and clinical outcome in ovarian cancer has not been studied. In the present study, we investigated the expression of PRL-3 in 119 ovarian cancers and 30 normal ovarian tissues by immunohistochemistry with an anti-PRL-3 mouse monoclonal antibody 3B6, and analyzed its relationship with clinicopathologic factors and survival. The results demonstrated that PRL-3 expression was significantly higher in ovarian cancers compared to normal ovarian tissues (P<0.001). PRL-3 expression is not correlated with patient age, menstruation, tumor size, histological type, residual tumor, or other clinical findings. The patients with PRL-3-positive tumors had a significant poor prognosis than those with PRL-3-negative tumors. Univariate analysis identified PRL-3 expression as a poor outcome predictor (HR 1.925, 95% CI, 1.046-3.544, P=0.035). Multivariate analysis indicated that PRL-3 expression was an independent prognostic factor of borderline significance (HR 1.695, 95% CI, 0.914-3.145, P=0.094). Our results suggest that PRL-3 may serve as a valuable marker for diagnosis of ovarian cancer and as a potential independent prognostic factor for ovarian cancer.