Xuqing Wang

Connective tissue growth factor enhances the migration of gastric cancer through downregulation of E-cadherin via the NF-κB pathway.

Local invasion and distant metastasis are difficult problems for surgical intervention and treatment in gastric cancer. Connective tissue growth factor (CTGF/CCN2) was considered to have an important role in this process. In this study, we demonstrated that expression of CTGF was significantly upregulated in clinical tissue samples of gastric carcinoma (GC) samples. Forced expression of CTGF in AGS GC cells promoted their migration in culture and significantly increased tumor metastasis in nude mice, whereas RNA interference‐mediated knockdown of CTGF in GC cells significantly inhibited cell migration in vitro. We disclose that CTGF downregulated the expression of E‐cadherin through activation of the nuclear factor‐κappa B (NF‐κB) pathway. The effects of CTGF in GC cells were abolished by dominant negative IκappaB. Collectively, these data reported here demonstrate CTGF could modulate the NF‐κappaB pathway and perhaps be a promising therapeutic target for gastric cancer invasion and metastasis. (Cancer Sci 2011; 102: 104–110)

CTGF is overexpressed in papillary thyroid carcinoma and promotes the growth of papillary thyroid cancer cells

Connective tissue growth factor (CTGF or CCN2), which belongs to the CCN family, is a secreted protein. It has been implicated in various biological processes, such as cell proliferation, migration, angiogenesis, and tumorigenesis. In this study, we found that CTGF expression level was elevated in primary papillary thyroid carcinoma (PTC) samples and correlated with clinical features, such as metastasis, tumor size, and clinical stage. Overexpression of CTGF in PTC cells accelerated their growth in liquid culture and soft agar as well as protecting PTC cells from apoptosis induced by IFN-gamma treatment. Downregulation of CTGF in PTC cells inhibits cell growth in liquid culture and soft agar and induces the activation of caspase pathway and sensitized PTC cells to apoptosis. Our data suggest that CTGF plays an important role in PTC progression by supporting tumor cell survival and drug resistance, and CTGF may be used as a potential tumor marker for PTC diagnosis.

Cyclooxygenase 2 promoted the tumorigenecity of pancreatic cancer cells.

Pancreatic cancer is one of the leading causes of cancer-related death in the world. It is very urgent to find new therapeutic targets and improve the treatment. Cyclooxygenase 2 (Cox2), a regulator of inflammation signaling, has been found to be involved in tumorigenesis of various tumor types. However, its biological functions in pancreatic cancer cells are not fully understood. Here, we found that the expression of Cox2 was elevated in pancreatic cancer tissues compared with that in the paired normal tissues. The over-expression of Cox2 in pancreatic cancer cells promoted cell proliferation and migration, while the knockdown of the expression of Cox2 inhibited the tumorigenesis of pancreatic cancer cells in vitro and in vivo. Mechanistically, Cox2 regulated the expression of multiple genes involved in cell growth, migration, and cell apoptosis. Taken together, our study revealed the pivotal function of Cox2 in pancreatic cancer, and Cox2 might be an important therapeutic target for the treatment.

Secreted protein acidic and rich in cysteine inhibits the growth of human pancreatic cancer cells with G1 arrest induction

Aberrant secreted protein acidic and rich in cysteine (SPARC) expression has been reported to play an important role in the tumor development. However, the pattern and the role of SPARC in pancreatic cancer remain largely unknown. Therefore, we further deciphered the role of SPARC played in pancreatic cancer. We first evaluated the SPARC expression in human pancreatic cancer tissues and pancreatic cancer cells. Then we forced expression and silenced SPARC expression in pancreatic cancer cell lines MIA PaCa2 and PANC-1, respectively, using lentivirus vectors. We characterized the stable cells in vitro. In this study, we found that SPARC expression was weak in cancer cells in specimens which negatively correlated with the expression level of phosphorylated pRB and poorer outcome. Moreover, our results demonstrated that SPARC negatively regulated pancreatic cell growth in vitro. Furthermore, we disclosed that the activation of p53 and p27Kip1 may involve in the effect of SPARC on pancreatic cancer cells. SPARC is downregulated in pancreatic cancer cells and retards the growth of pancreatic cancer cell. Taken together, these results indicate SPARC may be a potential target for pancreatic cancer therapy.

CCN1 promotes tumorigenicity through Rac1/Akt/NF-κB signaling pathway in pancreatic cancer

Aberrant CCN1 expression has been reported to play an important role in the tumor development. However, the pattern and the role of CCN1 in pancreatic cancer remain largely unknown. Therefore, we further deciphered the role CCN1 played in pancreatic cancer. We first evaluated the CCN1 expression in human pancreatic cancer tissues and pancreatic cancer cells. Then we forced expression and silenced CCN1 expression in pancreatic cancer cell lines MIA PaCa2 and PANC-1 respectively, using lentivirus vectors. We characterized the stable cells in vitro and in vivo using a nude mouse xenograft model. In this study, we found that CCN1 expression was significantly higher in cancer specimens which positively correlated with the expression level of phosphorylated Akt and p65. and poorer outcome. Moreover, our results demonstrated that CCN1 positively regulated pancreatic cell growth in vitro and in vivo and helped cancer cells resist to tumor necrosis factor alpha-induced apoptosis. Furthermore, we disclosed that activation of CCN1/ras-related c3 botulinum toxin substrate 1 (Rac1)/V-akt murine thymoma viral oncogene homolog (Akt)/nuclear factor-kappa B pathway inhibited apoptosis in pancreatic cancer cells. CCN1 is upregulated in pancreatic cancer and promotes the survival of pancreatic cancer cells. Taken together, these results indicate that CCN1 may be a potential target for pancreatic cancer therapy.

FOXC2 is up-regulated in pancreatic ductal adenocarcinoma and promotes the growth and migration of cancer cells

The transcriptional factor Forkhead box protein C2 (FOXC2) was recently demonstrated to be up-regulated in various cancer types. However, its expression profile and the biological functions in pancreatic cancer remain unknown. In this study, we examined the expression pattern of FOXC2 in pancreatic ductal adenocarcinoma (PDAC) tissues and investigated the functions of FOXC2 in the progression of PDAC. It was found that the expression of FOXC2 was up-regulated in PDAC samples. Forced expression of FOXC2 promoted the growth and migration of the PDAC cells, while knocking down the expression of FOXC2 inhibited the growth and migration of the PDAC cells. Moreover, FOXC2 was found to interact with beta-catenin and promote cell growth by activating beta-catenin/TCF signaling. Taken together, this study demonstrated the oncogenic roles of FOXC2 in PDAC, and FOXC2 might be a therapeutic target for PDAC.

Up-regulation of UHRF1 by oncogenic Ras promoted the growth, migration, and metastasis of pancreatic cancer cells.

Ubiquitin-like with PHD and ring finger domains 1 (UHRF1) has been reported as a marker for the differential diagnosis of pancreatic cancer and chronic pancreatitis. However, the expression pattern and biological functions of UHRF1 in the progression of pancreatic cancer are not fully understood. In this study, it was found that the expression of UHRF1 was significantly up-regulated in pancreatic cancer samples compared to their adjacent normal tissues. Meanwhile, the expression of UHRF1 was inversely correlated with the survival of pancreatic cancer patients. Moreover, in the biological function studies, UHRF1 was shown to promote the growth, migration, and metastasis of pancreatic cancer cells in vitro and in vivo. Mechanistically, the expression of UHRF1 was induced by oncogenic Ras in both pancreatic cancer mouse model and cultured cells. Taken together, our study demonstrated that UHRF1 played an oncogenic role in the progression of pancreatic cancer, and UHRF1 might be a promising target for the treatment of pancreatic cancer.

CARF activates beta-catenin/TCF signaling in the hepatocellular carcinoma.

Overactivation of Ras signaling is very common in the hepatocellular carcinoma (HCC) due to its constitutive active mutation, which makes it a big challenge to target Ras signaling. Therefore, identifying effectors downstream of Ras signaling would benefit the development of novel therapeutic strategies. In this study, it was found that the expression of CARF (collaborate of ARF) was induced by oncogenic RasV12. The expression of CARF was up-regulated in both HCC mouse model (Alb-Cre; P53f/f; Loxp-Stop-Loxp-RasG12D) and human HCC clinical samples. Overexpression of CARF promoted the growth and migration of HCC cells, while knocking down the expression of CARF inhibited the growth and migration of HCC cells. In the mechanism study, CARF was found to interact with beta-catenin, impaired the interaction between beta-catenin and ICAT, and activated beta-catenin/TCF signaling. Moreover, knocking down the expression of CARF inhibited the tumorigenesis in the HCC mouse model. Taken together, this study revealed the oncogenic functions of CARF in the tumorigenesis of HCC by activating beta-catenin/TCF signaling, and suggested CARF might be a therapeutic target in the treatment of HCC.

Prolyl hydroxylase 3 inhibited the tumorigenecity of gastric cancer cells.

Gastric cancer is one of the most common malignancies and the second leading cause of cancer‐related death in the world, and it is very urgent to develop novel therapeutic strategies. Although HIF‐1α is the most highly characterized target of prolyl hydroxylase 3 (PHD3), PHD3 has been shown to regulate several signal pathways independent of HIF‐1α. Here, we found that the expression of PHD3 was decreased in the clinical gastric cancer samples and reversely correlated with tumor size and tumor stage. Over‐expression of PHD3 in the gastric cancer cells significantly inhibited cell growth in vitro and in vivo, while knockdown the expression of PHD3 promoted the tumorigenecity of gastric cancer cells. Mechanistically, it showed that PHD3 downregulated the expression of beta‐catenin and inhibited beta‐catenin/T‐cell factor (TCF) signaling. Taken together, our findings demonstrate that PHD3 inhibits gastric cancer by suppressing the beta‐catenin/TCF signaling and PHD3 might be an important therapeutic target in gastric cancer. Copyright