Cofilin-1 (CFL1) and Arp3 expression in 46 squamous cell and adenosquamous carcinomas (SC/ASCs) and 80 adenocarcinomas (ACs) were measured by using immunohistochemistry. Positive CFL1 and Arp3 expression were significantly associated with large tumor size, high TNM stage, lymph node metastasis, and decreased overall survival in both SC/ASC and AC patients (p < .001). Multivariate Cox regression analysis showed that positive CFL1 and Arp3 expression are independent poor-prognostic factors for both SC/ASC and AC patients. Our study suggested that positive CFL1 and Arp3 expression are closely related to tumor progression, metastasis, and poor prognosis of gallbladder cancer.
Overexpression of ErbB2 is associated with poor prognosis in breast cancer. Targeting of ErbB2 is a very common therapeutic strategy in ErbB2-overexpressed breast cancer. Herceptin is the first approved and most widely used agent for ErbB2-targeting therapy in breast cancer. Even though the clinical application has been performed for more than 10 years, the exact mechanism underlying how Herceptin exhibits its effects has not been fully elucidated. In this study, we found that Herceptin could inhibit the expression of survivin in ErbB2-overexpressed cell lines. Overexpression of survivin could abrogate the inhibition of cell growth induced by Herceptin. Herceptin could reduce survivin expression at the transcriptional level. The b-catenin/ /T-cell factor (TCF) pathway played a very crucial role in this cascade. We found that Herceptin could reduce tyrosine phosphorylation levels of ErbB2 and b-catenin. Herceptin treatment induced degradation of b-catenin protein, resulting in reduced binding affinity of b-catenin/ /TCF4 to the promoter region of survivin. When we cross-mutated the TCF4 binding sites in the promoter region of survivin, the reduction of survivin promoter activity almost diminished. Taken together, we showed that Herceptin could inhibit survivin expression through the ErbB2-b-catenin/ /TCF4-survivin pathway in ErbB2-overexpressed breast cancer cells. This indicates that there may be a new cascade axis from ErbB2 to survivin. (Cancer Sci 2010; 101: 1156-1162 E rbB2, a member of human epidermal growth factor receptor family, also known as her2/neu/EGFR2, plays a key role in the regulation of cell proliferation, survival, and differentiation. Amplification of the ErbB2 gene and up-regulation of the ErbB2 protein level is common in breast cancer. The overall ErbB2-positive rate is about 22.2% (10-74%) in breast cancer tissues reported during the past 10 years.(1) ErbB2 overexpression implies poor clinical prognosis and therapeutic response.(1,2) Many approaches targeting ErbB2 have been followed in the treatment of breast cancer with overexpressed ErbB2, such as antibodies against ErbB2 protein, small molecule inhibitors of ErbB2 tyrosine kinases, and also the novel ErbB2 vaccines.Herceptin (Trastuzumab), a monoclonal antibody against ErbB2, is the most widely used agent for patients with ErbB2-positive breast cancer. Great successes have been achieved with Herceptin in the treatment of ErbB2-positive breast cancer. Combination of the targeted therapies with other traditional therapies has shown significant increases in time to disease progression and overall survival in the treatment of ErbB2-positive breast cancer.(1,3) Herceptin could inhibit cell growth through interfering with the function of ErbB2, and stop the ErbB2 triggered-downstream signaling networks. Although the exact mechanism of how Herceptin functions is not fully understood, it is known that Herceptin can inhibit pathways including the mitogen-activated protein kinase (MAPK) pathway and phosphatidylinositol-3-OH kinase (PI3K)/AKT path...
The clinicopathological characteristics of squamous cell/adenosquamous carcinoma (SC/ASC) of the gallbladder have not been well documented, and no prognosis marker has been identified because of the rare occurrence of this gallbladder cancer subtype. In this study, we examined ACE2 and FZD1 expression in 46 SC/ASCs and 80 adenocarcinomas using immunohistochemistry and further analyzed their correlations with clinicopathological characteristics. We demonstrated that positive FZD1 and negative ACE2 expression were significantly associated with large tumor size, high TNM stage, lymph node metastasis and invasion of SC/ASC and AC. Univariate Kaplan-Meier analysis showed that positive FZD1 and negative ACE2 expression as well as differentiation, tumor size, TNM stage, lymph node metastasis, invasion, and surgical curability were closely associated with decreased overall survival in both SC/ASC (p < 0.001) and AC (p < 0.001) patients. The average survival time in SC/ASC and AC patients with FZD1(-)ACE2(+) expression was significantly longer than that in patients with FZD1(+)ACE2(-) or FZD1(+)ACE2(+) (p < 0.01). Multivariate Cox regression analysis showed that positive FZD1 and negative ACE2 expression are independent poor-prognostic factors for both SC/ASC and AC patients. In addition, FZD1 expression positively, but ACE2 expression negatively correlated with the expression of CA19-9 in SC/ASC and AC. Our study suggested that positive FZD1 and negative ACE2 expression are closely related to the expression of CA19-9; clinical, pathological, and biological behaviors; as well as poor-prognosis of gallbladder cancer.
The clinicopathological and biological characteristics of squamous cell/adenosquamous carcinoma (SC/ASC) of the gallbladder remain to be fully elucidated, due to the fact that it is a rare gallbladder cancer subtype. In the current study, the expression of minichromosome maintenance complex component 2 (MCM2) and HIV-1 tat interactive protein 2 (TIP30) was measured in 46 cases of SC/ASC and 80 adenocarcinomas (AC) using immunohistochemistry. Positive MCM2 and negative TIP30 expression were significantly associated with large tumor size, high TNM stage, invasion, lymph node metastasis and lack of surgical curability in SC/ASC and AC. Positive MCM2 and negative TIP30 expression were significantly associated with poor differentiation in AC, whereas only MCM2 was correlated with differentiation in SC/ASC. Univariate Kaplan-Meier analysis demonstrated that positive MCM2 and negative TIP30 expression, the degree of differentiation, tumor size, TNM stage, invasion, lymph node metastasis and surgical curability were significantly associated with post-operative survival in patients with SC/ASC and AC. Multivariate Cox regression analysis demonstrated that positive MCM2 and negative TIP30 expression, the degree of differentiation, tumor size, TNM stage, invasion, lymph node metastasis and lack of surgical curability were also independent predictors of poor prognosis in patients with SC/ASC and AC. These data suggest that positive MCM2 and negative TIP30 expression are closely correlated with the clinical, pathological and biological parameters, in addition to poor prognosis in patients with gallbladder cancer.
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