The glucose-regulated proteins (GRPs) are stress-inducible chaperones that mostly reside in the endoplasmic reticulum or the mitochondria. Recent advances show that the GRPs have functions that are distinct from those of the related heat shock proteins, and they can be actively translocated to other cellular locations and assume novel functions that control signalling, proliferation, invasion, apoptosis, inflammation and immunity. Mouse models further identified their specific roles in development, tumorigenesis, metastasis and angiogenesis. This Review describes their discovery and regulation, as well as their biological functions in cancer. Promising agents that use or target the GRPs are being developed, and their efficacy as anticancer therapeutics is also discussed.

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Glucose-regulated proteins in cancer: molecular mechanisms and therapeutic potential

Advanced gastric cancer – Slow but steady progress

Endoplasmic reticulum stress in cerebral ischemia

Tubulin proteins, as components of the microtubule cytoskeleton perform critical cellular functions throughout all phases of the cell cycle. Altered tubulin isotype composition of microtubules is emerging as a feature of aggressive and treatment refractory cancers. Emerging evidence highlighting a role for tubulin isotypes in differentially influencing microtubule behaviour and broader functional networks within cells is illuminating a complex role for tubulin isotypes regulating cancer biology and chemotherapy resistance. This review focuses on the role of different tubulin isotypes in microtubule dynamics as well as in oncogenic changes that provide a survival or proliferative advantage to cancer cells within the tumour microenvironment and during metastatic processes. Consideration of the role of tubulin isotypes beyond their structural function will be essential to improving the current clinical use of tubulin-targeted chemotherapy agents and informing the development of more effective cancer therapies.

An Emerging Role for Tubulin Isotypes in Modulating Cancer Biology and Chemotherapy Resistance

Background 
Defects of autophagy and endoplasmic reticulum (ER) stress are related to many diseases and tumors. However, only a few studies have examined hepatocellular carcinoma (HCC) as related to these processes. Therefore, in this study, we investigated the expression and extent of autophagy and ER stress-related markers in HCC and their influence on clinical characteristics and prognosis for each protein.


Methodology 
The expression of autophagy-related markers (LC3 and Beclin-1) and ER stress-related markers (GRP78 and CHOP) was analyzed by immunohistochemistry on tissues from completely resected specimens of 190 HCC patients. Their influence on clinicopathologic features and prognosis were evaluated using the chi-square test and Kaplan-Meier analysis. Correlations of each protein were determined by Spearman's correlation analysis. 


Principal Findings 
LC3 expression was not correlated with TNM, BCLC stage, or Edmonson-Steiner grading, whereas it was correlated with longer overall survival (OS) (p = 0.039) and tended to be related with longer time to recurrence (TTR) (p=0.068) although it did not show statistical significance. Multivariate analysis indicated that LC3 expression was a significantly independent prognostic factor of OS (HR, 0.42; 95% CI, 0.22-0.80; p-value=0.009) and TTR (HR, 0.54; 95% CI, 0.33–0.90; p=0.017). Expression of LC3 in advanced stages of TNM (III) (p=0.045) and Edmonson-Steiner Grades (III and IV) (p=0.043) was correlated with longer survival, but not in the early stages. A positive correlation was not observed between the expression of autophagy-related markers and ER stress-related markers.


Conclusion 
Our results suggest that the expression and extent of LC3 might be a strong prognostic factor of HCC, especially in patients with surgical resection.

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The Autophagy-Related Marker LC3 Can Predict Prognosis in Human Hepatocellular Carcinoma

The purpose of this study was to detect the expressions of GRP78 and Bax in human non-small cell lung cancer (NSCLC) tissues, to analyze their correlations with carcinogenesis and the development of NSCLC, and to investigate the relationship of GRP78 expression to metastasis and apoptosis in the NSCLC cell line HCC827. The positive expression rates of GRP78 and Bax in NSCLC lung tissues were 59.7% and 34.7% by RT-PCR, respectively. The mRNA and protein expression levels of GRP78 in NSCLC tissues were significantly higher than that in the relatively normal surrounding lung tissues (p   0.05). The mRNA expression level of GRP78 and the mRNA expression level of Bax in human NSCLC tissues were negatively correlated (r = −0.353, p = 0.002). After transfection of GRP78 siRNA in HCC827 cells, the GRP78 protein expression level was significantly decreased (p < 0.01), while the Bax protein expression level was significantly increased (p < 0.01); the number of cells that passed through the Transwell chamber was significantly less in the non-transfected control group compared to the transfected control group (p < 0.01). The number of apoptotic cells was significantly greater in the non-transfected control group compared to the transfected control group (p < 0.01). The expression levels of GRP78 and Bax were related to the carcinogenesis, development and metastasis of NSCLC. GRP78 expression with siRNA interference in the human NSCLC cell line HCC827 can reduce metastasis and promote apoptosis in HCC827 cells.

Expressions of GRP78 and Bax associate with differentiation, metastasis, and apoptosis in non-small cell lung cancer

OBJECTIVE: The purpose of this study was to evaluate the value of vascular endothelial growth factor-A and E-cadherin expression as well as other confirmed prognostic factors in predicting the clinical outcome after definitive surgery of pathologic stage I non-small cell lung cancer. METHODS: One hundred and eighty-five consecutive and non-selected patients who underwent definitive surgery for stage I non-small cell lung cancer in our institute were included in this study. Formalin-fixed paraffin-embedded specimens were stained for vascular endothelial growth factor-A and E-cadherin and the correlation between the staining, its clinicopathological parameters and its prognostic power were analyzed statistically. RESULTS: Of the 185 patients studied, 92 cases (49.7%) were strongly positive for vascular endothelial growth factor-A. Vascular endothelial growth factor-A expression was only related to visceral pleural involvement (P < 0.001). A total of 95 carcinomas (51.4%) were E-cadherin-negative tumors. E-cadherin expression correlated with histology (P < 0.001), tumor size (P = 0.001) and visceral pleural involvement (P < 0.001). In univariate analysis by log-rank test, gender, tumor size, lymphovascular invasion, visceral pleural involvement, vascular endothelial growth factor-A expression and E-cadherin expression were significant prognostic factors (P = 0.003, 0.042, 0.026, 0.035, 0.008 and 0.006, respectively). In multivariate analysis, gender, vascular endothelial growth factor-A and E-cadherin expression maintained its independent prognostic influence on overall survival (P = 0.013, <0.001 and 0.036, respectively). CONCLUSIONS: Expression of vascular endothelial growth factor-A is related to visceral pleural involvement, and E-cadherin expression correlates with histology, tumor size and visceral pleural involvement. Multivariate analysis confirmed gender, vascular endothelial growth factor-A and E-cadherin expression were significant predictive factors for overall survival in completely resected pathologic stage I non-small cell lung cancer.

/pdf/prognostic-impact-of-vascular-endothelial-growth-factor-a-23p4wdh3tv.pdf

Prognostic impact of vascular endothelial growth factor-A and E-cadherin expression in completely resected pathologic stage I non-small cell lung cancer.

Objective: This Phase II study was conducted to evaluate the effects of irinotecan plus capecitabine in patients with advanced gastric cancer (AGC) who had received a first-line therapy of 5-fluorouracil/platinum regimen. Methods: Patients received capecitabine 1000 mg/m 2 b.i.d. on days 1 –1 4 followed by a 7-day rest period, and irinotecan 100 mg/m 2 was administered through a 90 min intravenous infusion on days 1 and 8, based on a 3-week cycle. Results: Forty-six (95.8%) of the 48 patients were assessable for response. Thirteen cases of partial response were confirmed, response rate of 27.1% (95% CI, 14.5 –3 9.7%). The median follow-up period was 25.2 months. The median time to progression and overall survival for all patients were 4.1 months (95% CI, 3.4–4.8 months) and 7.6 months (95% CI, 5.1 –1 0.1 months). Grade 3 diarrhea and hand-foot syndrome occurred in eight (17.4%) and two (4.3%) patients, respectively. The most common Grade 3/4 hematological adverse event was neutropenia in four (8.7%) patients. There were no treatment-related deaths during this study. Conclusion: Irinotecan plus capecitabine was a relatively active and tolerable regimen as a second-line chemotherapy for AGC. Further investigation of this regimen is warranted, including the addition of new biological agents such as bevacizumab or cetuximab to improve the salvage regimen.

/pdf/irinotecan-plus-capecitabine-as-a-second-line-treatment-2mkdv9qjvz.pdf

Maoquan Li

Papers

Expressions of GRP78 and Bax associate with differentiation, metastasis, and apoptosis in non-small cell lung cancer

Prognostic impact of vascular endothelial growth factor-A and E-cadherin expression in completely resected pathologic stage I non-small cell lung cancer.

Irinotecan plus capecitabine as a second-line treatment after failure of 5-fluorouracil and platinum in patients with advanced gastric cancer.