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Nuclear heat shock protein 110 expression is associated with poor prognosis and chemotherapy resistance in gastric cancer.

ABSTRACT: Heat shock protein (HSP) expression is induced by the exposure to stress, such as fever, oxidative stress, chemical exposure, and irradiation. In cancer, HSP promotes the survival of malignant cells by inhibiting the induction of apoptosis. In colorectal cancer, a loss-of-function mutation of HSP110 (HSP110?E9) has been identified. HSP110?E9 inhibits the nuclear translocation of wild-type HSP110, which is important for its chaperone activity and anti-apoptotic effects. The patients carrying HSP110?E9 mutation exhibit high sensitivity to anticancer agents, such as oxaliplatin and 5-fluorouracil. There is still insufficient information about HSP110 localization, the clinicopathological significance of HSP110 expression, and its association with chemotherapy resistance in gastric cancer. Here, we found that high nuclear expression of HSP110 in gastric cancer tissues is associated with cancer progression, poor prognosis, and recurrence after adjuvant chemotherapy. In vitro results showed that HSP110 suppression increases the sensitivity to 5-fluorouracil and cisplatin of human gastric cancer cell lines. Our results suggest that nuclear HSP110 may be a new drug sensitivity marker for gastric cancer and a potential molecular therapeutic target for the treatment of gastric cancer patients with acquired anticancer drug resistance.

SUBMITTER: Kimura A

PROVIDER: S-EPMC4951298 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Nuclear heat shock protein 110 expression is associated with poor prognosis and chemotherapy resistance in gastric cancer.

Kimura Akiharu A Ogata Kyoichi K Altan Bolag B Yokobori Takehiko T Ide Munenori M Mochiki Erito E Toyomasu Yoshitaka Y Kogure Norimichi N Yanoma Toru T Suzuki Masaki M Bai Tuya T Oyama Tetsunari T Kuwano Hiroyuki H

Oncotarget 20160401 14

Heat shock protein (HSP) expression is induced by the exposure to stress, such as fever, oxidative stress, chemical exposure, and irradiation. In cancer, HSP promotes the survival of malignant cells by inhibiting the induction of apoptosis. In colorectal cancer, a loss-of-function mutation of HSP110 (HSP110ΔE9) has been identified. HSP110ΔE9 inhibits the nuclear translocation of wild-type HSP110, which is important for its chaperone activity and anti-apoptotic effects. The patients carrying HSP1 ...[more]

PMID: 26943774

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Project description:Heat shock proteins (HSPs) are evolutionarily conserved chaperones occurring in virtually all living organisms playing a key role in the maintenance of cellular homeostasis. They are constitutively expressed to prevent and repair protein damage following various physiological and environmental stressors. HSPs are overexpressed in various types of cancers to provide cytoprotective function, and they have been described to influence prognosis and response to therapy. Moreover, they have been used as a tumor marker in blood serum biochemistry and they represent a potentially promising therapeutic target. To clarify prognostic significance of two canonical HSPs (27 and 70) and less known HSP110 (previously known as HSP105) in colorectal carcinoma (CRC), we retrospectively performed HSP immunohistochemistry on tissue microarrays from formalin-fixed paraffin-embedded tumor tissue from 297 patients with known follow-up. Survival analysis (univariate Kaplan-Meier analysis with the log-rank test and multivariate Cox regression) revealed significantly shorter overall survival (OS, mean 5.54 vs. 7.07, p = 0.033) and borderline insignificantly shorter cancer specific survival (CSS, mean 6.3 vs. 7.87 years, p = 0.066) in patients with HSP70+ tumors. In the case of HSP27+ tumors, there was an insignificantly shorter OS (mean 6.36 vs. 7.13 years, p = 0.2) and CSS (mean 7.17 vs. 7.95 years, p = 0.2). HSP110 showed no significant impact on survival. Using Pearson's chi-squared test, there was a significant association of HSP27 and HSP70 expression with advanced cancer stage. HSP27+ tumors were more frequently mismatch-repair proficient and vice versa (p = 0.014), and they occurred more often in female patients and vice versa (p = 0.015). There was an enrichment of left sided tumors with HSP110+ compared to the right sided (p = 0.022). In multivariate Cox regression adjusted on the UICC stage, grade and right/left side; both HSPs 27 and 70 were not independent survival predictors (p = 0.616 & p = 0.586). In multivariate analysis, only advanced UICC stage (p = 0) and right sided localization (p = 0.04) were independent predictors of worse CSS. In conclusion, from all three HSPs examined in our study, only HSP70 expression worsened CRC prognosis, although stage-dependent. The contribution of this article may be seen as a large survival analysis of HSPs 27 and 70 and the largest analysis of HSP110 described in CRC.

Project description:Background: Lysyl oxidase (LOX) is a key enzyme for the cross-linking of collagen and elastin in the extracellular matrix. This study evaluated the prognostic role of LOX in gastric cancer (GC) by analyzing the data of The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) dataset. Methods: The Wilcoxon rank-sum test was used to calculate the expression difference of LOX gene in gastric cancer and normal tissues. Western blot and immunohistochemical staining were used to evaluate the expression level of LOX protein in gastric cancer. Kaplan-Meier analysis was used to calculate the survival difference between the high expression group and the low expression group in gastric cancer. The relationship between statistical clinicopathological characteristics and LOX gene expression was analyzed by Wilcoxon or Kruskal-Wallis test and logistic regression. Univariate and multivariate Cox regression analysis was used to find independent risk factors affecting the prognosis of GC patients. Gene set enrichment analysis (GSEA) was used to screen the possible mechanisms of LOX and GC. The CIBERSORT calculation method was used to evaluate the distribution of tumor-infiltrating immune cell (TIC) abundance. Results: LOX is highly expressed in gastric cancer tissues and is significantly related to poor overall survival. Wilcoxon or Kruskal-Wallis test and Logistic regression analysis showed, LOX overexpression is significantly correlated with T-stage progression in gastric cancer. Multivariate Cox regression analysis on TCGA and GEO data found that LOX (all p < 0.05) is an independent factor for poor GC prognosis. GSEA showed that high LOX expression is related to ECM receptor interaction, cancer, Hedgehog, TGF-beta, JAK-STAT, MAPK, Wnt, and mTOR signaling pathways. The expression level of LOX affects the immune activity of the tumor microenvironment in gastric cancer. Conclusion: High expression of LOX is a potential molecular indicator for poor prognosis of gastric cancer.

Project description:The switching/sucrose non-fermenting (SWI/SNF) chromatin remodeling complexes use the energy of ATP hydrolysis to remodel nucleosomes and modulate transcription, which plays an important role in tumors by regulating epigenetics. SWI/SNF Related, Matrix Associated, Actin Dependent Regulator of Chromatin, Subfamily C, Member 1 (SMARCC1) has dual roles in tumors but its role in gastric cancer remains unclear. This study was aimed to find the role of SMARCC1 in gastric cancer. SMARCC1 expression across various tumors from The Cancer Genome Atlas was analyzed using TIMER 2.0 (http://timer.comp-genomics.org/). SMARCC1 mRNA expression profiles in gastric cell lines and gastric tissues were compared with normal tissues and analyzed in the Cancer Cell Line Encyclopedia, Oncomine, and Gene Expression Omnibus databases. SMARCC1 mRNA and protein were then examined in fresh gastric cancer tissues and compared with adjacent normal tissues using quantitative real-time PCR, western blotting, and immunohistochemistry. Associations between SMARCC1 expression and clinicopathological factors, overall survival, and disease-free survival were further evaluated using 130 gastric cancer samples harvested from patients after radical total gastrectomy or subtotal gastrectomy at the Xiangya Hospital of Central South University (Changsha, China). SMARCC1 was frequently upregulated in gastric cancer cells and tissues. SMARCC1 overexpression was significantly associated with tumor size (P=0.002), differentiation (P=0.006), depth of invasion (P=0.001), lymph node involvement (P=0.016), and TNM stage (P=0.007). Furthermore, univariate and multivariate Cox analysis revealed that high SMARCC1 expression, depth invasion, lymph node involvement, and TNM stage were independent risk factors for both overall and disease-free survival in gastric cancer patients (all P<0.05). Kaplan-Meier survival analysis revealed that high SMARCC1 expression predicted poor prognosis in gastric cancer patients (P<0.01). High SMARCC1 expression contributes to poor prognosis in gastric cancer patients. SMARCC1 may be a prognostic biomarker and therapeutic target in gastric cancer.

Dataset Information

Nuclear heat shock protein 110 expression is associated with poor prognosis and chemotherapy resistance in gastric cancer.

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Nuclear heat shock protein 110 expression is associated with poor prognosis and chemotherapy resistance in gastric cancer.

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