• HER2
• drug resistance
• gastric cancer
• trastuzumab

• 3′-untranslated region
• AU-rich element, mRNA stability
• non-small cell lung cancer, XB130

• Diabetes mellitus
• Diabetic skin ulcers
• PI3K/Akt signalling pathway
• XB130

• Gastric cancer
• PTEN
• Resistance
• Trastuzumab
• XB130

• Humans
• Animals
• Mice
• Trastuzumab/pharmacology
• Trastuzumab/therapeutic use
• Proto-Oncogene Proteins c-akt/metabolism
• Phosphatidylinositol 3-Kinases/metabolism
• Stomach Neoplasms/drug therapy
• Stomach Neoplasms/genetics
• Stomach Neoplasms/metabolism
• Signal Transduction
• Adaptor Proteins, Signal Transducing/genetics
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• PTEN Phosphohydrolase

• EMT
• XB130
• adapter protein
• cell growth
• miRNA

• EMT
• SP+ cells
• cancer stem cells
• mammosphere

• Apoptosis
• Hepatocellular Carcinoma
• PI3K/Akt
• TRAIL
• XB130

Gastric cancer is common in developing regions, and we hope to find out an economical but practical prognostic indicator. It was reported that pre-treatment peripheral neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), as well as differentiation status, were associated with cancer progression. Hence, we introduced a novel combined Neutrophil/platelet/lymphocyte/differentiation Score (cNPLDS) to improve the prediction value of palliative chemotherapeutic response in advanced gastric cancer.

According to statistical sample size estimation, 136 primary diagnosed unresectable advanced ptaients were included for a retrospective study. The follow-up end-point was progression free survival (PFS) during the first-line palliative chemotherapy. Differentiation stratified patients into well, medium and poor groups by score 1 to 3, while patients with neither elevated NLR and PLR, only one elevated, or both elevated were of the combined NLR-PLR score (cNPS) 1 to 3, respectively. The cNPLDS was calculated by multiplying the tumor differentiation score and cNPS.

Determined by the receiver operating characteristic (ROC) curve, the optimal cut-off points for NLR and PLR were 3.04 and 223. Through univariate analysis and survival analysis, poor differentiation, high NLR, high PLR, high cNPS, and high cNPLDS respectively indicated inferior PFS during the first-line palliative chemotherapy. Patients were furhter classified into low to high risk groups by cNPLDS. Groups of elevated NLR, PLR, cNPS, and cNPLDS showed lower disease control rate. Compared to other parameters, cNPLDS significantly improved the accuracy in predicing the first-progression.

This study indicates that the novel parameter cNPLDS is superior to NLR or PLR alone, or even cNPS, in predicting the first-line chemosensitivity in advanced gastric cancer.

• Chemosensitivity
• Gastric cancer
• Neutrophil-to-lymphocyte ratio
• Platelet-to-lymphocyte ratio
• Tumor differentiation

XB130 is a cytosolic adaptor protein involved in various physiological processes and oncogenesis of certain malignancies, but its role in the development of prostate cancer remains unclear. In current study, we examined XB130 expression in prostate cancer tissues and found that XB130 expression was remarkably increased in prostate cancer tissues and significantly correlated with increased prostate specific antigen (PSA), free PSA (f-PSA), prostatic acid phosphatase (PAP) and T classification. Patients with highly expressed XB130 had significantly decreased survival, which suggested XB130 as a possible prognostic indicator for prostate cancer. In vitro experiments showed that reduced XB130 expression restrained tumor growth both in vitro and in vivo. Furthermore, XB130 knockdown hindered transition of G1 to S phase in prostate cancer cell line DU145 and LNCap, which might contribute to the inhibition of cellular proliferation. Results from transwell assay demonstrated that downregulation of XB130 may attenuate invasion and metastasis of prostate cancer. Semiquantitative analysis of Western blot suggested that decreased XB130 expression was accompanied by diminished Akt signaling and EMT process. Thus, above observations suggest that XB130 may be a novel molecular marker and potent therapeutic target for prostate cancer.

• Akt
• XB130
• adaptor protein
• invasion
• proliferation

• cell death
• cell proliferation
• inflammatory response
• septic response
• transgenic mouse

Proliferation of bronchioalveolar stem cells (BASCs) is essential for epithelial repair. XB130 is a novel adaptor protein involved in the regulation of epithelial cell survival, proliferation and migration through the PI3K/Akt pathway. To determine the role of XB130 in airway epithelial injury repair and regeneration, a naphthalene-induced airway epithelial injury model was used with XB130 knockout (KO) mice and their wild type (WT) littermates. In XB130 KO mice, at days 7 and 14, small airway epithelium repair was significantly delayed with fewer number of Club cells (previously called Clara cells). CCSP (Club cell secreted protein) mRNA expression was also significantly lower in KO mice at day 7. At day 5, there were significantly fewer proliferative epithelial cells in the KO group, and the number of BASCs significantly increased in WT mice but not in KO mice. At day 7, phosphorylation of Akt, GSK-3β, and the p85α subunit of PI3K was observed in airway epithelial cells in WT mice, but to a much lesser extent in KO mice. Microarray data also suggest that PI3K/Akt-related signals were regulated differently in KO and WT mice. An inhibitory mechanism for cell proliferation and cell cycle progression was suggested in KO mice. XB130 is involved in bronchioalveolar stem cell and Club cell proliferation, likely through the PI3K/Akt/GSK-3β pathway.

• PI3K/Akt signaling
• bronchioalveolar duct junction
• naphthalene
• small airway injury and repair
• transgenic mice

• XB130
• actin filament-associated protein
• adaptor proteins
• cancer

AIM: To investigate the expression of actin filament-associated protein 1-like 2 (AFAP-1L2) in different pancreatic cancer cell lines, the effect of AFAP-1L2 on cell proliferation, cell cycle and apoptosis, and the possible mechanism.

METHODS: Western blot and real-time quantitative PCR (qRT-PCR) were used to detect the AFAP-1L2 protein and mRNA expression in PANC-1, MiaPaCa-2, Colo-357, BXPC-3, SW1990 and CFPAC-1 cell lines (having different differentiation degrees). siAFAP-1L2 plasmid was constructed and transfected into MiaPaCa-2 cell to downregulate the expression of AFAP-1L2. Proteins of the phosphatidylinositol 3 kinase/protein kinase B (PI3K/Akt) pathway were detected by Western blot and qRT-PCR after siAFAP-1L2 transfection. Proliferation was detected by MTT assay. Cell cycle and apoptosis were detected by flow cytometry.

RESULTS: Western blot and qRT-PCR analyses showed that AFAP-1L2 was correlated with differentiation degree, and the expression was higher in cell lines with low differentiation than in those with moderate or high differentiation. PI3KCA protein expression in the siAFAP-1L2 group was lower than that in the MOCK and siRNA control groups (F = 20.16, P = 0.0022). α-Akt mRNA expression in the siAFAP-1L2 group was higher than that in the MOCK and siRNA control groups (F = 7.719, P = 0.0219); α-pAkt protein expression in the siAFAP-1L2 group was lower than that in MOCK and siRNA control groups (F = 5.507, P = 0.0439). PI3KCA mRNA expression in the siAFAP-1L2 group was lower than that in the AFAP-1L2 and siRNA control groups (F = 20.16, P = 0.0022). α-Akt mRNA expression in the siAFAP-1L2 group was higher than that in the MOCK and siRNA control groups (F = 6.068, P = 0.0362); α-pAkt mRNA expression in the siAFAP-1L2 group was lower than that in the MOCK and siRNA control groups (F = 10.33, P = 0.0114). MTT assay showed that the proliferation of MiaPaCa-2 cells at 48 h, 72 h, and 96 h was inhibited after siAFAP-1L2 transfection (F = 3.924, P < 0.05; F = 6.812, P < 0.01; F = 7.003, P < 0.01). Flow cytometry showed that cells in G₁ phase were increased, but those in G₂ and S phases were decreased (F = 4.87, 5.26, 4.94, P < 0.05 for all). The apoptosis rate of MiaPaCa-2 cell was increased after siAFAP-1L2 transfection (F = 7.231, P < 0.01).

CONCLUSION: AFAP-1L2 expression is associated with cell differentiation. AFAP-1L2 modulates cell proliferation, cell cycle and apoptosis via the PI3K/Akt pathway. AFAP-1L2 is a target candidate for pancreatic cancer therapy.

• Cell differentiation
• Actin filament-associated protein 1-like 2
• Pancreatic cancer
• Proliferation
• Apoptosis

• Breast cancer
• XB130
• apoptosis
• gemcitabine
• invasion

• Adaptor Proteins, Signal Transducing/genetics
• Adaptor Proteins, Signal Transducing/metabolism
• Antimetabolites, Antineoplastic/pharmacology
• Apoptosis
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Breast Neoplasms/genetics
• Breast Neoplasms/metabolism
• Breast Neoplasms/mortality
• Breast Neoplasms/pathology
• Breast Neoplasms/therapy
• Carcinoma, Ductal, Breast/genetics
• Carcinoma, Ductal, Breast/metabolism
• Carcinoma, Ductal, Breast/mortality
• Carcinoma, Ductal, Breast/secondary
• Carcinoma, Ductal, Breast/therapy
• Cell Movement
• Cell Proliferation
• Chi-Square Distribution
• Deoxycytidine/analogs & derivatives
• Deoxycytidine/pharmacology
• Disease-Free Survival
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Immunohistochemistry
• Kaplan-Meier Estimate
• MCF-7 Cells
• Mastectomy
• Middle Aged
• Multivariate Analysis
• Neoplasm Invasiveness
• Neoplasm Staging
• Proportional Hazards Models
• RNA Interference
• Risk Factors
• Signal Transduction
• Time Factors
• Transfection
• Treatment Outcome
• Up-Regulation
• Gemcitabine

• Osteosarcoma
• RNA interference
• XB130
• immunohistochemistry
• prognosis

• Adaptor Proteins, Signal Transducing/biosynthesis
• Adolescent
• Adult
• Animals
• Biomarkers, Tumor/analysis
• Blotting, Western
• Bone Neoplasms/metabolism
• Bone Neoplasms/mortality
• Bone Neoplasms/pathology
• Child
• Disease-Free Survival
• Female
• Heterografts
• Humans
• Immunohistochemistry
• Kaplan-Meier Estimate
• Male
• Mice
• Mice, Nude
• Osteosarcoma/metabolism
• Osteosarcoma/mortality
• Osteosarcoma/pathology
• Prognosis
• Proportional Hazards Models
• Retrospective Studies
• Transfection
• Young Adult

• Gastric cancer
• Lymphangiogenesis
• Metastasis-associated in colon cancer-1
• Vascular endothelial growth factor-C/D
• c-Met signaling

The repair and regeneration of airway epithelium is important for maintaining homeostasis of the respiratory system. XB130 is an adaptor protein involved in the regulation of cell proliferation, survival and migration. In the human trachea, XB130 is expressed on the apical site of ciliated epithelial cells. We hypothesize that XB130 may play a role in epithelial repair and regeneration after injury. Xb130 knockout (KO) mice were generated, and a mouse isogenic tracheal transplantation model was used. Adult Xb130 KO mice did not show any significant anatomical and physiological phenotypes in comparison with their wild type (WT) littermates. The tracheal epithelium in Xb130 KO mice, however, was significantly thicker than that in WT mice. Severe ischemic epithelial injury was observed immediately after the tracheal transplantation, which was followed by epithelial cell flattening, proliferation and differentiation. No significant differences were observed in terms of initial airway injury and apoptosis. However, at Day 10 after transplantation, the epithelial layer was significantly thicker in Xb130 KO mice, and associated with greater proliferative (Ki67+) and basal (CK5+) cells, as well as thickening of the connective tissue and fibroblast layer between the epithelium and tracheal cartilages. These results suggest that XB130 is involved in the regulation of airway epithelial differentiation, especially during airway repair after injury.

• Adaptor Proteins, Signal Transducing/genetics
• Adaptor Proteins, Signal Transducing/physiology
• Animals
• Cell Differentiation/physiology
• Epithelial Cells/cytology
• Mice
• Mice, Knockout
• Microfilament Proteins/genetics
• Microfilament Proteins/physiology
• Trachea/cytology

• MOP-119514 Canadian Institutes of Health Research
• MOP-13270 Canadian Institutes of Health Research
• MOP-42546 Canadian Institutes of Health Research

XB130 is a newly discovered adaptor protein for intracellular signal transduction; it is involved in gene regulation, cell proliferation, cell survival, cell migration, and tumorigenesis. However, its expression and role in pancreatic ductal adenocarcinoma (PDAC) have not been investigated. The present study was designed to clarify the prognostic significance of XB130 expression in PDAC.

A total of 76 consecutive patients with surgically resected PDAC were retrospectively reviewed. XB130 expression was detected by immunohistochemical analysis on the paraffin-embedded tumour sections. Correlation between the expression of XB130 and clinicopathological parameters was analyzed.

XB130 expression was significantly upregulated in PDAC(56.5%, 43/76) compared to normal pancreas (0%, 0/15; P < 0.05). Increased XB130 expression was correlated with lymph node metastasis (P = 0.017), distant metastasis (P = 0.0024), high tumour-node-metastasis (TNM) stage (P =0.001), and high tumour grade (P = 0.013). The survival of 43 patients with high XB130 expression was significantly worse than that of the 33 patients with low XB130 expression (P = 0.001). Univariate analysis showed that high XB130 expression (P = 0.0045), tumour size (P = 0.024), distant metastasis (P = 0.003), TNM stage (P = 0.002) and lymphatic metastasis (P = 0.016) were independent prognostic factors of postoperative survival. Multivariate analysis using the Cox proportional hazards model showed that high XB130 expression and distant metastasis (P = 0.0239) were significant independent risk factors.

XB130 was overexpressed in the PDAC. XB130 is a promising pathological marker for the prediction of outcome in patients with PDAC.

Golgi phosphoprotein 3 (GOLPH3) has been validated as a potent oncogene involved in the progression of many types of solid tumors, and its overexpression is associated with poor clinical outcome in many cancers. However, it is still unknown the association of GOLPH3 expression with the prognosis of colorectal cancer (CRC) patients who received 5-fluorouracil (5-FU)-based adjuvant chemotherapy.

The expression of GOLPH3 was determined by qRT-PCR and immunohistochemistry in colorectal tissues from CRC patients treated with 5-FU based adjuvant chemotherapy after surgery. The association of GOLPH3 with clinicopathologic features and prognosis was analysed. The effects of GOLPH3 on 5-FU sensitivity were examined in CRC cell lines.

GOLPH3 expression was elevated in CRC tissues compared with matched adjacent noncancerous tissues. Kaplan-Meier survival curves indicated that high GOLPH3 expression was significantly associated with prolonged disease-free survival (DFS, P = 0.002) and overall survival (OS, P = 0.011) in patients who received 5-FU-based adjuvant chemotherapy. Moreover, multivariate analysis showed that GOLPH3 expression was an independent prognostic factor for DFS in CRC patients treated with 5-FU-based chemotherapy (HR, 0.468; 95%CI, 0.222-0.987; P = 0.046). In vitro, overexpression of GOLPH3 facilitated the 5-FU chemosensitivity in CRC cells; while siRNA-mediated knockdown of GOLPH3 reduced the sensitivity of CRC cells to 5-FU-induced apoptosis.

Our results suggest that GOLPH3 is associated with prognosis in CRC patients treated with postoperative 5-FU-based adjuvant chemotherapy, and may serve as a potential indicator to predict 5-FU chemosensitivity.

XB130 has been reported to be expressed by various types of cells such as thyroid cancer and esophageal cancer cells, and it promotes the proliferation and invasion of thyroid cancer cells. Our previous study demonstrated that XB130 is also expressed in gastric cancer (GC), and that its expression is associated with the prognosis, but the role of XB130 in GC has not been well characterized.

In this study, we investigated the influence of XB130 on gastric tumorigenesis and metastasis in vivo and in vitro using the MTT assay, clonogenic assay, BrdU incorporation assay, 3D culture, immunohistochemistry and immunofluorescence. Western blot analysis was also performed to identify the potential mechanisms involved.

The proliferation, migration, and invasion of SGC7901 and MNK45 gastric adenocarcinoma cell lines were all significantly inhibited by knockdown of XB130 using small hairpin RNA. In a xenograft model, tumor growth was markedly inhibited after shXB130-transfected GC cells were implanted into nude mice. After XB130 knockdown, GC cells showed a more epithelial-like phenotype, suggesting an inhibition of the epithelial-mesenchymal transition (EMT) process. In addition, silencing of XB130 reduced the expression of p-Akt/Akt, upregulated expression of epithelial markers including E-cadherin, α-catenin and β-catenin, and downregulated mesenchymal markers including fibronectin and vimentin. Expression of oncoproteins related to tumor metastasis, such as MMP2, MMP9, and CD44, was also significantly reduced.

These findings indicate that XB130 enhances cell motility and invasiveness by modulating the EMT-like process, while silencing XB130 in GC suppresses tumorigenesis and metastasis, suggesting that it may be a potential therapeutic target.

• MACC1
• gastric cancer
• invasion
• prognosis
• proliferation

XB130, a novel adaptor protein, promotes cell growth by controlling expression of many related genes. MicroRNAs (miRNAs), which are frequently mis-expressed in cancer cells, regulate expression of targeted genes. In this present study, we aimed to explore the oncogenic mechanism of XB130 through miRNAs regulation. We analyzed miRNA expression in XB130 short hairpin RNA (shRNA) stably transfected WRO thyroid cancer cells by a miRNA array assay, and 16 miRNAs were up-regulated and 22 miRNAs were down-regulated significantly in these cells, in comparison with non-transfected or negative control shRNA transfected cells. We chose three of the up-regulated miRNAs (miR-33a, miR-149 and miR-193a-3p) and validated them by real-time qRT-PCR. Ectopic overexpression of XB130 suppressed these 3 miRNAs in MRO cells, a cell line with very low expression of XB130. Furthermore, we transfected miR mimics of these 3 miRNAs into WRO cells. They negatively regulated expression of oncogenes (miR-33a: MYC, miR-149: FOSL1, miR-193a-3p: SLC7A5), by targeting their 3′ untranslated region, and reduced cell growth. Our results suggest that XB130 could promote growth of cancer cells by regulating expression of tumor suppressive miRNAs and their targeted genes.