The clinicopathological significance of Jagged1 and DLL4 in gallbladder cancer.

PURPOSE: Gallbladder cancers (GBCs) are highly aggressive gastrointestinal cancers with high mortality. Biological markers for the diagnosis, prognosis, and targeted therapy of GBCs have not been established. METHODS: The protein expression of Jagged1 and DLL4 in 80 adenocarcinomas (AC) and 46 squamous cell/adenosquamous carcinomas (SC/ASCs) was measured using immunohistochemistry. RESULTS: Positive Jagged1 and DLL4 expression in both SC/ASC and AC was significantly associated with poor differentiation, large tumor size, invasion, metastasis, and low surgical curability. Univariate Kaplan-Meier analysis showed that positive Jagged1 and DLL4 expression was significantly associated with mean survival of SC/ASC and AC patients. Multivariate Cox regression analysis showed that positive Jagged1 and DLL4 expression, as well as poor differentiation, large tumor size, high TNM stage, invasion, lymph node metastasis, and low surgical curability are independent poor prognostic factors in both SC/ASC and AC patients. CONCLUSIONS: Positive Jagged1 and DLL4 expression is closely correlated with severe clinicopathological characteristics and poor prognosis in patients with SC/ASC and patients with AC.

MCM2 and TIP30 are prognostic markers in squamous cell/adenosquamous carcinoma and adenocarcinoma of the gallbladder.

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 HIV­1 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 Kaplan­Meier 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 post­operative 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.

SHP2 and UGP2 are Biomarkers for Progression and Poor Prognosis of Gallbladder Cancer.

Biomarkers for the diagnosis, prognosis, and targeting therapy of gallbladder cancers are not clinically available. This study demonstrated that the percentage of cases with positive SHP2 and UGP2 expression significantly correlated with the percentage of cases with positive vimentin, ß-catenin, MMP2, MMP9, and Ki-67 expression, large tumor size, high TNM stage, lymph node metastasis, and survival in patients with adenocarcinomas and squamous cell/adenosquamous carcinomas. Positive SHP2 and UGP2 expression are independent poor-prognostic factors in both types of tumors. Our study suggested that positive SHP2 and UGP2 expression correlated with clinicopathological and biological behaviors, and poor-prognosis of gallbladder cancer.

Overexpression of Thy1 and ITGA6 is associated with invasion, metastasis and poor prognosis in human gallbladder carcinoma.

Gallbladder cancer (GBC) is a rare but highly aggressive cancer for which no well-accepted prognostic biomarkers have been identified. Thymus cell antigen 1 (Thy1), also known as cluster of differentiation (CD)90, and integrin α6 (ITGA6), also known as CD49f, are important molecules in cancer and putative markers of various stem cell types. However, their role in GBC remains to be elucidated. In the present study, Thy1 and ITGA6 expression status in clinical GBC samples, which comprised squamous cell/adenosquamous carcinoma (SC/ASC) and adenocarcinoma (AC) subtypes, was investigated. The associations between Thy1 and ITGA6 expression and clinical parameters and survival rate were analyzed separately. The THY1 and ITGA6 messenger RNA levels were significantly higher in both SC/ASC and AC tissues than in adjacent non-tumor tissues (all P<0.001). These results were subsequently confirmed by immunohistochemical analyses. Overexpression of Thy1 and ITGA6 was correlated with poor differentiation, large tumor size, lymph node metastasis and great invasiveness in SC/ASC (Thy1, P=0.045, P=0.005, P=0.003 and P=0.009, respectively, and ITGA6, P=0.029, P=0.011, P=0.009 and P=0.004, respectively) and AC (Thy1, P=0.027, P<0.001, P=0.003 and P 0.004, respectively, and ITGA6, P=0.002, P=0.003, P=0.006 and P=0.006, respectively). Both Thy1 and ITGA6 were expressed at higher levels in AC with advanced tumor-node-metastasis stage (TNM) than in AC with low TNM stage (P=0.001 and P=0.018, respectively). In addition, patients with elevated Thy1 or ITGA6 expression had shorter overall survival than those with negative Thy1 or ITGA6 expression. Multivariate Cox regression analysis demonstrated that Thy1 (SC/ASC, P=0.001 and AC, P=0.005) and ITGA6 (both P=0.003) were independent predictors of poor prognosis in both SC/ASC and AC patients. In conclusion, Thy1 and ITGA6 could be clinical prognostic markers for GBC.

The Expression of Notch 1 and Notch 3 in Gallbladder Cancer and Their Clinicopathological Significance.

Gallbladder cancers (GBCs) are highly malignant gastrointestinal cancers. The biological makers for the prognosis and targeting therapy of GBCs have not been established. The protein expression of Notch 1 and Notch 3 in 46 squamous cell/adenosquamous carcinomas (SC/ASCs) and 80 adenocarcinomas (AC) was measured using immunohistochemistry. Positive Notch 1 and Notch 3 expression in both SC/ASC and AC was significantly associated with large tumor size, invasion, metastasis, and low surgical curability (P < 0.05 or P < 0.01). Univariate Kaplan-Meier analysis showed that positive Notch 1 and Notch 3 expression was significantly associated with mean survival of SC/ASC and AC patients (P < 0.01 or P < 0.001). Multivariate Cox regression analysis showed that positive Notch 1 and Notch 3 expression, as well as low differentiation, large tumor size, high TNM stage, invasion, lymph node metastasis, and surgical curability are independent poor-prognostic factors in both SC/ASC and AC patients. Positive Notch 1 and Notch 3 expression is closely correlated with severe clinicopathological characteristics and poor prognosis in both SC/ASC and AC patients.

LATS2-mediated YAP1 phosphorylation is involved in HCC tumorigenesis.

YAP (yes-associated protein) is a transcriptional co-activator that acts downstream of the Hippo signaling pathway and regulates multiple cellular processes, including proliferation and apoptosis. Although YAP plays an important role in various tumors, the underlying mechanism in hepatocellular carcinoma (HCC) tumorigenesis remains unclear. In this study, we observed that the LATS2 was highly expressed in Bel-7402 and HepG2 cell lines, and LATS2 protein level was negatively correlated with YAP1 in HCC cells. And then, we inhibited LATS2 expression by transfecting with siRNA. Western blot and Immunofluorescent staining analysis demonstrated that LATS2 inhibition decreased the dephosphorylation of YAP1 protein and promoted YAP1 nuclear accumulation in HCC cells. Moreover, Immunoprecipitation assay results also indicated that Yap binds directly to TEAD2 and LATS2 inhibition-mediated dephosphorylation increased the YAP1/TEAD2 association, leading to YAP1/TEAD2 transcriptional activation, which in turn upregulated cell invasion in HCC cells. Taken together, our current data indicated a new regulatory mechanism of YAP1 by the LATS2-mediated phosphorylation that was involved in HCC tumorigenesis.

ATP5b and ß2-microglobulin are predictive markers for the prognosis of patients with gallbladder cancer.

The differences in clinical, pathological, and biological characteristics between adenocarcinoma (AC) and squamous cell/adenosquamous carcinoma (SC/ASC) of the gallbladder have not been well documented. This study investigates the clinical and pathological associations of ATP5B and ß2M with benign and malignant lesions of the gallbladder. In this study, ATP5B and ß2M expression in 46 SC/ASCs and 80 ACs were examined using immunohistochemistry. The rate of ATP5B positive expression was significantly lower, while the rate of ß2M expression was significantly higher, in AC and SC/ASC than in gallbladder adenomas, gallbladder polyps, or gallbladder epithelium with stone (P < 0.01). More SC/ASCs had larger tumor mass and good differentiation compared to ACs. Positive ß2M and negative ATP5B expression were significantly associated with large tumor size, high TNM stage, lymph node metastasis, and invasion of SC/ASCs and ACs. Univariate Kaplan-Meier analysis showed that positive ß2M (P < 0.05 or P < 0.001) expression and negative ATP5B (P < 0.001) expression were significantly associated with decreased overall survival in both SC/ASC and AC patients. Multivariate Cox regression analysis showed that negative ATP5B expression is an independent-prognostic factor for poor prognosis in both SC/ASC (P < 0.01) and AC (P < 0.001) patients. Positive ß2M expression is an independent-prognostic factor for poor prognosis in AC (P < 0.05) patients. Our study suggested that positive ß2M expression or loss of ATP5B expression in tumor tissues is closely related to the metastasis, invasion, and poor-prognosis of gallbladder cancer.

DNA-PKcs and Ku70 are predictive markers for poor prognosis of patients with gall bladder malignancies.

Gall bladder cancers (GBCs) are highly resistant to radiotherapy and chemotherapy. Unfortunately, the key molecular mechanisms responsible for therapeutic resistance have not been identified. In this study, the expression of DNA-PKcs and Ku70 in 46 squamous cell/adenosquamous carcinomas (SC/ASCs) and 80 adenocarcinomas (ACs) were examined by immunohistochemical analysis. Positive DNA-PKcs and Ku70 expression were significantly associated with less lymph node metastasis, invasion, and low TNM stage of SC/ASCs and ACs. Univariate Kaplan-Meier analysis showed that loss of DNA-PKcs and Ku70 expression significantly correlated with decreased survival in both SC/ASC and AC patients. Multivariate Cox regression analysis showed that loss of DNA-PKcs and Ku70 expression was an independent poor prognostic predictor in both SC/ASC and AC patients. Our study suggested that DNA-PKcs and Ku70 are tumor suppressors, and loss of DNA-PKcs and Ku70 expression is an important biological marker for metastasis, invasion, and prognosis of GBC. Currently, there is no implication of DNA-PKcs and Ku70 expression in chemoresistance or radioresistance in GBC.

TSG101 and PEG10 are prognostic markers in squamous cell/adenosquamous carcinomas and adenocarcinoma of the gallbladder.

The clinicopathological characteristics of squamous cell/adenosquamous carcinoma (SC/ASC) are currently not well documented, and as the prevalence of SC/ASC is uncommon in gallbladder cancers, a prognostic marker has not yet been found. In the present study, the expression of tumor susceptibility gene (TSG) 101 and paternally expressed gene (PEG) 10 was assessed in 46 SC/ASCs and 80 adenocarcinomas (ACs) using immunohistochemistry, and the samples were further analyzed to examine correlations with the clinicopathological characteristics. It was demonstrated that positive TSG101 and PEG10 expression were significantly associated with large tumor size, high tumor-node-metastasis (TNM) stage, lymph node metastasis, invasion and no resection (only biopsy) of SC/ASC and AC. The univariate Kaplan-Meier analysis showed that positive TSG101 and PEG10 expression, and differentiation, tumor size, TNM stage, lymph node metastasis, invasion and surgical curability, is closely associated with a decreased overall survival in SC/ASC and AC patients (P<0.05 or P<0.001). The multivariate Cox regression analysis identified that positive TSG101 and PEG10 expression are independent factors for a poor-prognosis in SC/ASC and AC patients. The present study indicates that positive TSG101 and PEG10 expression are closely associated with the clinical, pathological and biological behaviors, and a poor prognosis in gallbladder cancer.

EphB1 and Ephrin-B, new potential biomarkers for squamous cell/adenosquamous carcinomas and adenocarcinomas of the gallbladder.

Squamous cell/adenosquamous carcinoma (SC/ASC) of the gallbladder are rare tumors and there are few clinical reports in the literature. Herein we report our clinical experience with 46 patients with SC/ASC and 80 with adenocarcinoma (AC). Expression of EphB1 and Ephrin-B in each tumor was determined using immunohistochemical methods for determination of correlations with prognosis. There was no difference in EphB1 and Ephrin-B expression between SC/ASC and AC tumors (P>0.05), but greater expression in those less than 3 cm in diameter, stage I or II (TNM stage), with no lymph node metastases, with no local invasion and treated with radical resection was apparent. Expression of EphB1 (P<0.05) and Ephrin-B (P<0.01) was higher in well differentiated than in poorly differentiated AC tumors. Kaplan-Meier survival analysis indicated that degree of differentiation, tumor diameter, lymph node metastases, local invasion, surgical approach and expression rate of EphB1 and Ephrin-B were closely related to the survival of SC/ASC (P<0.05) and AC patients (P<0.01). Patients with tumors that positive expressed EphB1 and Ephrin-B, whether it is SC/ASC (P SC/ASC =0.000) or AC (P AC =0.000 or P AC =0.002) had longer survival than those negative expression. Cox multivariate analysis indicated a negative correlation between expression of EphB1 or Ephrin-B and overall survival. Hence, EphB1 and Ephrin-B could be regarded as independent good prognostic factorsand important biological markers for SC/ASC and AC of gallbladder.

N-cadherin and P-cadherin are biomarkers for invasion, metastasis, and poor prognosis of gallbladder carcinomas.

Gallbladder cancer (GBC) is a rare, but highly aggressive cancer. The most common type of gallbladder cancer is adenocarcinoma (AC), while squamous cell/adenosquamous carcinoma (SC/ASC) is a rare type of gallbladder cancer. The clinicopathologic and biological characteristics of SC/ASC have not been well documented. In this study, the protein expression of N-cadherin and P-cadherin in 46 SC/ASCs and 80 ACs was measured using immunohistochemistry. We demonstrated that positive N-cadherin and P-cadherin expression were significantly associated with large tumor size, invasion, and lymph node metastasis of both SC/ASC and AC. In contrast, positive N-cadherin and P-cadherin expression were significantly associated with differentiation and TNM stage in only AC. Univariate Kaplan-Meier analysis showed that positive N-cadherin and P-cadherin expression, differentiation, tumor size, TNM stage, invasion, lymph node metastasis, and surgical curability were significantly associated with overall survival in both SC/ASC and AC patients. Multivariate Cox regression analysis showed that positive N-cadherin and P-cadherin expression are independent poor-prognostic factors in both SC/ASC and AC patients. Our study suggested that positive N-cadherin and P-cadherin expression closely correlated with clinicopathological and biological behaviors, and poor-prognosis of gallbladder cancer.

A comparative study of clinicopathological significance, FGFBP1, and WISP-2 expression between squamous cell/adenosquamous carcinomas and adenocarcinoma of the gallbladder.

BACKGROUND: The differences in clinical, pathological, and biological characteristics between adenocarcinoma (AC) and squamous cell/adenosquamous carcinoma (SC/ASC) of gallbladder cancer have not been well documented. This study is to compare the clinicopathological characteristics and FGFBP1 and WISP-2 expression between AC and SC/ASC patients. METHODS: We examined FGFBP1 and WISP-2 expression in 46 SC/ASC and 80 AC samples using immunohistochemistry and analyzed their correlations with clinicopathological characteristics. RESULTS: SC/ASCs occur more frequently in older patients and often correspond to larger tumor masses than ACs. Positive FGFBP1 and negative WISP-2 expression were significantly associated with lymph node metastasis and invasion of SC/ASCs and ACs. In addition, positive FGFBP1 and negative WISP-2 expression were significantly associated with differentiation and TMN stage in ACs. Univariate Kaplan-Meier analysis showed that either elevated FGFBP1 (p < 0.001) or lowered WISP-2 (p < 0.001) expression was closely associated with decreased overall survival in both SC/ASC and AC patients. Multivariate Cox regression analysis showed that positive FGFBP1 expression (p = 0.001) or negative WISP-2 expression (p = 0.035 for SC/ASC and p = 0.009 for AC) is an independent predictor of poor prognosis in both SC/ASC and AC patients. We also revealed that differentiation, tumor size, TNM stage, lymph node metastasis, invasion, and surgical procedure were associated with survival of both SC/ASC and AC patients. CONCLUSION: Our study suggested that the overexpression of FGFBP1 or loss of WISP-2 expression is closely related to the metastasis, invasion and poor prognosis of gallbladder cancer.

Squamous cell/adenosquamous carcinomas and adenocarcinomas of the gallbladder: an immunohistochemistry study of prognostic markers.

Gallbladder cancers (GBCs) are highly aggressive and lethal diseases. However, the key molecular mechanisms responsible for the progression and prognosis of GBCs have not been identified. No biological markers for effectively identifying GBC subtypes have been reported. In this study the expression of keratin 19 (KRT19) and human achaete-scute homolog 1 (hASH1) proteins in 46 squamous cell/adenosquamous carcinomas (SC/ASC) and 80 adenocarcinomas (AC) were examined using immunohistochemistry. Negative KRT19 or positive hASH1 expression were significantly associated with lymph node metastasis, invasion and TNM stage of SC/ASC patients. In contrast, positive KRT19 and hASH1 expression were significantly associated with large tumor size, lymph metastasis, invasion, and TNM stage in AC patients. Univariate Kaplan-Meier analysis showed that loss of KRT19 or elevated hASH1 expression significantly correlated with decreased survival in SC/ASC patients. In contrast, positive KRT19 and hASH1 expression correlated with a shorter survival time in AC patients. Multivariate Cox regression analysis showed that negative KRT19 expression or positive hASH1 expression was an independent poor-prognostic predictor in SC/ASC, but positive KRT19 and hASH1 expression were poor-prognostic factors in AC patients. Our study suggested that hASH1 can be used to determine the malignancy of SC/ASC and AC tumors and is associated with poor prognosis. In contrast, KRT19 is a protective factor in AC patients but a sign of malignancy in SC/ASC patients.

ACE2 and FZD1 are prognosis markers in squamous cell/adenosquamous carcinoma and adenocarcinoma of gallbladder.

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.

Paxillin and carbonic anhydrase IX are prognostic markers in gallbladder squamous cell/adenosquamous carcinomas and adenocarcinomas.

AIMS: Squamous cell/adenosquamous carcinomas (SC/ASC) are rare subtypes of gallbladder cancers (GBCs). Clinical characteristics of SC/ASC have not been well documented, and no biological markers of GBC carcinogenesis, progression and prognosis are available. METHODS AND RESULTS: We measured paxillin and CAIX expression in 46 SC/ASCs and 80 adenocarcinomas (ACs) with immunohistochemistry and correlated these data with clinicopathological characteristics. Both paxillin expression and CAIX expression were associated significantly with larger tumours, a higher tumour-node-metastasis (TNM) stage, lymph node metastasis and invasiveness of SC/ASC and AC. Univariate Kaplan-Meier analysis confirmed that paxillin and CAIX expression were associated closely with decreased overall survival in SC/ASC (both P < 0.001) and AC (both P < 0.001). Multivariate Cox regression analysis confirmed that paxillin expression and CAIX expression both independently predicted poor prognosis in SC/ASC and AC patients. We also noted correlations with survival and tumour differentiation, tumour size, TNM stage, lymph node metastasis, tumour invasiveness and sample procurement methods. CONCLUSIONS: Paxillin expression and CAIX expression are both related to clinical/biological behaviour and poor prognosis of GBC.

Positive ALDH1A3 and negative GPX3 expressions are biomarkers for poor prognosis of gallbladder cancer.

BACKGROUND: Gallbladder cancers (GBCs) are highly aggressive cancers with high mortality. However, biological markers for the progression and prognosis of GBC are currently unavailable in the clinic. OBJECTIVE: To identify biomarkers for predicting GBC metastasis and prognosis. METHODS: We examined ALDH1A3 and GPX3 expressions in 46 squamous cell/adenosquamous carcinomas (SC/ASC) and 80 adenocarcinomas (AC) by using immunohistochemistry. RESULTS: Positive ALDH1A3 and negative GPX3 expressions were significantly associated with lymph node metastasis and invasion of SC/ASCs and ACs. Univariate Kaplan-Meier analysis showed that either positive ALDH1A3 (P < 0.001) or negative GPX3 (P < 0.001) expression significantly correlated with decreased overall survival in both SC/ASC and AC patients. Multivariate Cox regression analysis showed that positive ALDH1A3 expression or negative GPX3 expression was an independent poor-prognostic predictor in both SC/ASC and AC patients. CONCLUSIONS: Our study suggested that positive ALDH1A3 and negative GPX3 expressions are closely associated with clinical pathological behaviors and poor prognosis of gallbladder cancer.

Clinicopathological features and CCT2 and PDIA2 expression in gallbladder squamous/adenosquamous carcinoma and gallbladder adenocarcinoma.

BACKGROUND: Gallbladder cancer (GBC) is a relatively uncommon carcinoma among gastrointestinal cancers and usually has a rather poor prognosis. The most common subtype of GBC is adenocarcinoma (AC), which accounts for about 90% of GBC. Squamous carcinoma/adenosquamous carcinoma (SC/ASC) are comparatively rare histopathological subtypes of GBC. The clinicopathological features and biological behaviors of SC/ASC have not been well-characterized. No molecular biomarkers are currently available for predicting the progression, metastasis, and prognosis of the SC/ASC subtype of GBC. METHODS: We examined the expression levels of CCT2 and PDIA3 by immunohistochemistry (IHC) staining in human GBC tissue samples collected from 46 patients with SC/ASC and evaluated the clinicopathological significance of both CCT2 and PDIA3 expression in the SC/ASC subtypes of GBC by Kaplan-Meier analysis and multivariate Cox regression analysis. For comparison, we included specimens from 80 AC patients in our study to investigate the specificity of CCT2 and PDIA3 expression in GBC subtypes. RESULTS: We found that the positive expression of CCT2 and PDIA3 was significantly associated with clinicopathological features of both SC/ASC and AC specimens, including high TNM stage and lymph node metastasis. Univariate analysis revealed that the two-year survival rate was significantly lower for patients with positive expression of CCT2 and PDIA3 than for those with negative expression. Multivariate analysis also indicated that the positive expression of CCT2 and PDIA3 was negatively correlated with poor postoperative patient survival and positively correlated with high mortality. CONCLUSIONS: Our study suggests that positive expression of CCT2 or PDIA3 is associated with tumor progression and the clinical behavior of gallbladder carcinoma. Therefore, CCT2 and PDIA3 could be potentially important diagnostic and prognostic biomarkers for both SC/ASC and AC subtypes of GBC.

CFL1 and Arp3 are biomarkers for metastasis and poor prognosis of squamous cell/adenosquamous carcinomas and adenocarcinomas of gallbladder.

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.

Nectin-2 and DDX3 are biomarkers for metastasis and poor prognosis of squamous cell/adenosquamous carcinomas and adenocarcinoma of gallbladder.

The clinicopathological and biological characteristics of squamous cell/adenosquamous carcinoma (SC/ASC) of gallbladder have not been well documented because it is a rare subtype of gallbladder cancer. In this study, the protein expression of Nectin-2 and DDX3 in 46 SC/ASCs and 80 adenocarcinomas was measured using immunohistochemistry. We demonstrated that positive Nectin-2 and DDX3 expression was significantly associated with large tumor size, high TNM stage, and lymph node metastasis of SC/ASC and AC. Positive Nectin-2 and DDX3 expression was significantly associated with invasion and surgical curability of AC. Univariate Kaplan-Meier analysis showed that positive Nectin-2 and DDX3 expression, degree of differentiation, tumor size, TNM stage, invasion, lymph node metastasis, and surgical curability were significantly associated with post-operative survival in both SC/ASC and AC patients. Multivariate Cox regression analysis showed that positive Nectin-2 and DDX3 expression, degree of differentiation, tumor size, TNM stage, invasion, lymph node metastasis, and no surgical curability are independent poor-prognostic factors in both SC/ASC and AC patients. Our study suggested that positive Nectin-2 and DDx3 expression is closely correlated with clinical, pathological, and biological behaviors as well as poor-prognosis of gallbladder cancer.

ILK and PRDX1 are prognostic markers in squamous cell/adenosquamous carcinomas and adenocarcinoma of gallbladder.

Although the incidence of gallbladder cancers is low, they are highly aggressive tumors. Squamous cell/adenosquamous carcinoma (SC/ASC) is a rare subtype of gallbladder cancer. The clinical characteristics of SC/ASC have not been well documented, and no prognosis marker has been identified. In this study, we examined integrin-linked kinase (ILK) and peroxiredoxin-1 (PRDX1) expression in 46 SC/ASCs and 80 adenocarcinomas (ACs) by using immunohistochemistry and analyzed their correlations with clinicopathological characteristics. We demonstrated that positive ILK and PRDX1 expressions 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 ILK and PRDX1 expressions were closely associated with decreased overall survival in both SC/ASC (p < 0.001 and p = 0.005, respectively) and AC (p < 0.001) patients. Multivariate Cox regression analysis showed that positive ILK and PRDX1 expressions were an independent poor prognostic predictor in both SC/ASC and AC patients. We also revealed a similar significance of differentiation, tumor size, TNM stage, lymph node metastasis, invasion, and surgical curability with survival in SC/ASC and AC patients. Our study suggested that positive ILK and PRDX1 expressions are closely related to the progression and poor prognosis of gallbladder cancer.