High STMN1 level is associated with chemo-resistance and poor prognosis in gastric cancer patients.

BACKGROUND: Stathmin1 (STMN1) is a cytosolic phosphoprotein that regulates cellular microtubule dynamics and is known to have oncogenic activity. Despite several reports, its roles in gastric cancer (GC) remain unclear owing to a lack of analyses of highly metastatic cases. This study aimed to investigate STMN1 as a prognostic and predictive indicator of response to paclitaxel therapy in patients with GC, including inoperable cases. METHODS: Immunohistochemical analysis of STMN1 was performed on both operable (n=95) and inoperable GC (n=61) samples. The roles of STMN1 in cancer cell proliferation and sensitivity to a microtubule-targeting drug, paclitaxel, were confirmed by knockdown experiments using GC cell lines. RESULTS: Multivariate and Kaplan-Meier analyses demonstrated that high STMN1 was predictive of poor prognosis in both the groups. In the operable cohort, STMN1 expression correlated with cancer curability, recurrence, and resistance to adjuvant therapy. A correlation with paclitaxel resistance was observed in inoperable cases. Knockdown of STMN1 in GC cell lines inhibited proliferation and sensitised the cells to paclitaxel by enhancing apoptosis. CONCLUSIONS: STMN1 is a possible biomarker for paclitaxel sensitivity and poor prognosis in GC and could be a novel therapeutic target in metastatic GC.

High STMN1 Expression is Associated with Cancer Progression and Chemo-Resistance in Lung Squamous Cell Carcinoma.

BACKGROUND: Known as a microtubule-destabilizing protein, STMN1 (gene symbol: STMN1) regulates the dynamics of microtubules, cell cycle progress, and chemo-resistance against taxane agents. It is highly expressed in various human cancers and involved in cancer progression as well as poor prognosis. METHODS: Expression of STMN1 was examined by immunohistochemistry using FFPE tissue sections from 186 patients with lung squamous cell carcinoma (LSCC). Analysis of STMN1 suppression was performed for STMN1 small interfering RNA (siRNA)-transfected LSCC cell lines to determine the change in proliferation, invasive and apoptosis abilities, and paclitaxel sensitivity. RESULTS: The cytoplasmic STMN1 expression in LSCC was higher than in normal tissues. The high expression was significantly associated with vascular invasion (P = 0.0477) and poor prognosis. In addition, the proliferating and invasive abilities were decreased, and the apoptosis ability and paclitaxel sensitivity were increased in STMN1-suppressed LSCC cells compared with control cells. CONCLUSION: The results suggest that STMN1 is a prognostic factor that also is associated with caner progression and chemo-resistance. Therefore, STMN1 could be a predictor for poor prognosis and a potential therapeutic target in LSCC.

High expression of nucleobindin 2 is associated with poor prognosis in gastric cancer.

Nucleobindin 2 has been reported that its high expression is associated with poor outcome and promotes cell migration and lymph node metastasis in breast cancer, colon cancer, and prostate cancer. However, we aimed to investigate the nucleobindin 2 expression in gastric cancer tissues and adjacent non-tumor tissues and its potential relevance to clinicopathological factors and prognosis using immunohistochemical analysis. In our study, nucleobindin 2 level in gastric cancer tissues was higher than in non-tumor tissues. A high expression of nucleobindin 2 is significantly associated with tumor depth, lymph node metastasis, lymphatic invasion, venous invasion, and clinical stage. Furthermore, the expression level of nucleobindin 2 protein was independent predictor of progression-free survival. In summary, nucleobindin 2 might play a crucial role in gastric cancer development and could serve as an independent predictor of prognosis of gastric cancer patients.

Caspase14 expression is associated with triple negative phenotypes and cancer stem cell marker expression in breast cancer patients.

BACKGROUND AND OBJECTIVES: The Caspase14 (CASP14) was reported that the low expression of CASP14 in ovarian cancer and colon cancer was associated with cancer progression, on the other hand, that the CASP14 expression in breast cancer was higher than that of non-cancerous tissues. The purpose of this study is to determine the clinical significance of CASP14 in breast cancer. METHODS: We performed immunohistochemistry for CASP14, ER, PgR, HER2, Ki67, EGFR, CK5/6, CD44, CD24, ALDH1, claudins, and androgen receptor in 222 breast cancer patients including 55 TNBC cases, and evaluated the relationship of CASP14, above-mentioned markers, and prognosis. Using public microarray database of breast cancer, the prognostic value of CASP14 was calculated. RESULTS: High CASP14 expression was significantly associated with TNBC subtype (P = 0.015), nuclear grade (P = 0.006), Ki67, EGFR (P < 0.001, P = 0.016), ALDH1, CD44 and CD24 (P < 0.001, P < 0.001, P = 0.001) in 222 breast cancer cases, and the high expression of claudin1 (P = 0.017), and androgen receptor (P = 0.002) in TNBC cases was related to the high CASP14. According to the public database, survival in the high CASP14 breast cancer patients was shorter than low CASP14 patients. CONCLUSIONS: High CASP14 expression is a marker of breast cancer aggressiveness in association with proliferation, TNBC phenotype, and cancer stemness.

Nuclear PRMT1 expression is associated with poor prognosis and chemosensitivity in gastric cancer patients.

BACKGROUND: Metastatic and refractory gastric cancer (GC) are associated with a poor prognosis; therefore, the identification of prognostic factors and chemosensitivity markers is extremely important. Protein arginine methyltransferase 1 (PRMT1) may play a role in chemosensitivity/apoptosis induction via activation of the tumor suppressor forkhead box O1 (FOXO1). The purpose of this study was to clarify the expression of and relationship between PRMT1 and FOXO1 to evaluate the applicability of PRMT1 as a prognostic marker and a therapeutic tool in GC. METHODS: We investigated the clinical and functional significance of PRMT1 and FOXO1 in 195 clinical GC samples using immunohistochemistry. We performed suppression analysis of PRMT1 using small interfering RNA to determine the biological roles of PRMT1 in chemosensitivity. RESULTS: PRMT1 and FOXO1 in GC samples were predominantly expressed in the nucleus. Patients with lower PRMT1 expression (n = 131) had suppressed nuclear accumulation of FOXO1, higher recurrence after adjuvant chemotherapy, and poorer prognosis than those with higher PRMT1 expression (n = 64). PRMT1 downregulation in GC cells by RNA interference inhibited cisplatin and 5-fluorouracil sensitivity. The expression of phosphorylated FOXO1 and phosphorylated BCL-2 antagonist of cell death was upregulated in PRMT1 small interfering RNA groups. CONCLUSION: Our data suggest that the evaluation of PRMT1 expression in GC is a useful predictor of poor prognosis and recurrence after adjuvant chemotherapy. Moreover, these data suggest that PRMT1 is a promising therapeutic tool for overcoming refractory GC.

Nuclear PROX1 is Associated with Hypoxia-Inducible Factor 1α Expression and Cancer Progression in Esophageal Squamous Cell Carcinoma.

BACKGROUND: Transcription factor prospero homeobox 1 (PROX1) has been identified as a master regulator of lymphangiogenesis associated with metastasis. Although PROX1 expression has been investigated in several cancers, its clinical significance remains controversial and needs further validation. In this study, we investigated the clinical and functional significance of PROX1 and PROX1 regulator hypoxia-inducible factor 1α (HIF1α) in esophageal squamous cell carcinoma (ESCC). METHODS: A total of 117 samples from ESCC patients were analyzed for PROX1, HIF1α, and E-cadherin expression by immunohistochemistry; correlation with clinicopathological characteristics was determined. PROX1 function was evaluated in PROX1 small interfering RNA (siRNA)-transfected human ESCC cells in vitro by assessing cell proliferation and migration. RESULTS: PROX1 expression was higher in ESCC than in normal tissues. Patients with higher PROX1 expression (n = 26) had increased nuclear accumulation of HIF1α (p = 0.004) and more advanced metastasis, both lymph node (N factor; p = 0.09) and hematogenous (M factor; p = 0.04), than those with lower PROX1 expression (n = 91). In addition, high PROX1 and HIF1α expression correlated with low levels of E-cadherin, an epithelial cell marker. Analysis of overall and cancer-specific survival indicated that elevated PROX1 expression was significantly correlated with poor prognosis (p = 0.0064). PROX1 downregulation in ESCC cells inhibited cellular proliferation and migration (p < 0.05). Hypoxia restored PROX1 levels that were reduced by PROX1-specific siRNA. CONCLUSION: Our data suggest that high expression of PROX1 in ESCC could be used as an indicator of poor prognosis, and that PROX1 is a promising candidate molecular target for ESCC treatment.

Relationship between LAT1 expression and resistance to chemotherapy in pancreatic ductal adenocarcinoma.

PURPOSE: L-type amino acid transporter 1 (LAT1) is linked to tumor cell proliferation, angiogenesis, and survival in various human cancers. Although the expression of LAT1 was identified as a significant prognostic predictor after surgery in patients with pancreatic ductal adenocarcinoma (PDAC), little is known about the clinical significance of LAT1 as a chemotherapeutic resistance factor in PDAC. METHODS: A total of 110 patients with surgically resected PDAC were retrospectively reviewed as the training set. Immunohistochemical staining of resected tumor specimens was assessed using anti-LAT1 antibodies. In vitro analysis of chemotherapy resistance and LAT1 function using PDAC cell lines was also performed. RESULTS: The rate of high expression of LAT1 was 64.1% (71/110). The high expression of LAT1 protein was significantly associated with tumor differentiation, tumor depth (T factor), lymph node metastasis, venous invasion, recurrence, and clinical response. By multivariate analysis, LAT1 was validated as an independent prognostic factor for predicting worse survival after surgery. We analyzed the TCGA data set and obtained similar results that the survival rates of SLC7A5 high expression group were poorer than that of low expression group. LAT1 could successfully predict the outcome of patients who received adjuvant chemotherapy after surgery (n = 88) and systemic chemotherapy after recurrence (n = 56). All patients with high LAT1 expression were non-responders, whereas approximately 30% of the patients with low LAT1 expression responders (p = 0.0002). By analyzing the TCGA online database, it was found that LAT1 closely correlated with hypoxia-induced genes, such as PTGES, PYGL, and KPNA2. CONCLUSION: LAT1 as an independent prognostic marker is a potential molecular targeting gene to reduce chemoresistance and tumor growth in patients with PDAC, supported by our in vitro study.

Correlation of tumor-related immunity with 18F-FDG-PET in pulmonary squamous-cell carcinoma.

OBJECTIVES: 2-Deoxy-2-[fluorine-18] fluoro-d-glucose with positron emission tomography (18F-FDG-PET) is a clinically useful tool for cancer evaluation. 18F-FDG accumulation in tumor cells is known to be correlated with the presence of glucose transporter 1 (GLUT1) and hypoxia-inducible factor-1α (HIF-1α). Although anti-programmed death-1 (PD-1) antibody treatments have been approved, no suitable predictor of significant responders has been identified. Based on the existing information, we investigated the relationship between tumor immunity (including PD-L1) and 18F-FDG uptake in patients with surgically resected pulmonary squamous-cell carcinoma (SQC). MATERIALS AND METHODS: This study included 167 patients (153 men and 14 women) with SQC who underwent 18F-FDG PET. Tumor sections were stained by immunohistochemistry for GLUT1, HIF-1α, PD-L1, CD4, CD8, and Foxp3. The relationship between clinicopathological features and 18F-FDG uptake was analyzed. Student's t-test, the χ2 test, non-parametric Spearman's rank test and the Kaplan-Meier method were used to show associations between variables. RESULTS: The rate of positive PD-L1 expression was 79% (132/167), and PD-L1 expression was significantly associated with GLUT1 (P < 0.01), HIF-1α (P < 10-4), and CD8 (P < 1 × 10-3) expression. The SUVmax of 18F-FDG was significantly correlated with PD-L1 (P = 0.02) and GLUT1 (P < 0.01) expression. Multivariate analysis demonstrated that advanced stage, elevated PD-L1 expression, and elevated SUVmax were independent prognostic factors for predicting poor OS. Among patients with a high SUVmax, multivariate analysis confirmed that advanced stage and high PD-L1 expression were independent prognostic factors for poor OS; however, there was no significant difference among patients with a low SUVmax. CONCLUSION: High SUVmax on 18F-FDG-PET is associated with PD-L1 expression but is an independent prognostic factor for OS in our population of surgically resected pulmonary squamous-cell carcinoma.

High expression of carcinoembryonic antigen and telomerase reverse transcriptase in circulating tumor cells is associated with poor clinical response to the immune checkpoint inhibitor nivolumab.

The present study aimed to enrich circulating tumor cells (CTCs) from blood samples using a new size-sorting CTC chip. The present study also set out to identify a blood sensitivity marker for the immune checkpoint inhibitor nivolumab in patients with advanced, pre-treatment lung cancer. The CTC sorting efficacy of the chip was investigated and the large cell fraction of blood samples from 15 patients with pre-treatment lung cancer who were later administered nivolumab were purified. The expression levels of carcinoembryonic antigen (CEA), human Telomerase Reverse Transcriptase (hTERT), cytokeratin19 (CK19), and programmed death ligand-1 (PD-L1) were investigated to clarify the association between these CTC markers and the clinical response to nivolumab. The CTC chip effectively enriched cells from lung cancer cell line PC-9. The large cell fraction had a high expression of CEA and hTERT, with the former being significantly associated with the clinical response to nivolumab. The expression of CEA and hTERT in CTCs derived from the blood of a patient with lung cancer were also validated. The evaluation of CEA and possibly hTERT in CTCs collected by the CTC chip may represent a promising predictive blood marker for sensitivity to nivolumab. To the best of our knowledge this is the first report to describe the predictive CTC marker for nivolumab in pre-treatment patients.

Stathmin1 expression is associated with aggressive phenotypes and cancer stem cell marker expression in breast cancer patients.

Stathmin1 (STMN1) regulates progression in various cancers. The present study aimed to determine the relationship between STMN1 expression and several cancer-related markers in breast cancer. Using immunohistochemistry, we evaluated STMN1, estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, Ki-67, epidermal growth factor receptor (EGFR), CK5/6, CD44, CD24, aldehyde dehydrogenase 1, E-cadherin, epithelial cell adhesion molecule, and vimentin in 237 breast cancer patients and the clinical significance of STMN1. STMN1 expression was evaluated in 51 breast cancer cell lines, and the prognostic value of STMN1 was calculated. Higher STMN1 expression was detected in cancer tissues and was predominantly localized in the cytoplasm. High STMN1 expression was associated with the triple negative subtype, nuclear grade progression, high expression of Ki-67, EGFR, CK5/6, E-cadherin and high CD44/low CD24. According to gene expression-based outcome for breast cancer online and the Kaplan-Meier plotter, STMN1 expression was higher in basal-type cell lines than in luminal-type cell lines, and overall survival and post-progression survival in the high STMN1 expression breast cancer patients were shorter than in low STMN1 expression patients. High STMN1 expression is a possible marker of breast cancer aggressiveness in association with proliferation, phenotype and cancer stem cell type.

High Expression of MRE11-RAD50-NBS1 Is Associated with Poor Prognosis and Chemoresistance in Gastric Cancer.

BACKGROUND: The MRN complex of meiotic recombination 11 (MRE11), DNA repair protein Rad50 (RAD50) and Nijmegen breakage syndrome 1 (NBS1) proteins coordinate the detection and repair of DNA double-strand breaks (DSBs). DNA DSB repair-dependent chemoresistance likely has an effect on the treatment of human cancer. MATERIALS AND METHODS: We investigated the expression of MRN complex in human gastric cancer (GC) tissues using immunohistochemistry and analyzed its clinical significance and prognostic relevance. RESULTS: The expression of MRN complex was significantly associated with clinical factors including poorer prognosis and negatively associated with the expression of DNA damage marker phosphorylated H2A histone family, member X (γH2AX) in the nucleus. In the biopsy specimens, low expression of MRE11 correlated with good response to chemotherapy and surgical resection after down-staging by chemotherapy. Furthermore, the expression levels of MRE11 and RAD50 were independent predictors of surgical resection after chemotherapy. CONCLUSION: The high expression of MRN complex constituents could be a predictor for poor prognosis and chemoresistance in GC.