PRR11 Promotes Proliferation and Migration of Colorectal Cancer through Activating the EGFR/ERK/AKT Pathway via Increasing CTHRC1.

OBJECTIVE: Colorectal cancer (CRC) is a common prevalent malignant tumor globally. The prognosis of CRC patients remains poor due to a lack of effective treatment strategy. Proline-rich 11 (PRR11) is an emerging oncogene in cancers, while its effect in CRC remains unclear. Hence, the present study aimed to identify the function of PRR11 on CRC progression and study the detailed mechanism. METHODS: Cell proliferation ability was determined by Cell Counting Kit-8 (CCK-8) assay and 5-ethynyl-2'-deoxyuridine (EdU) staining. Transwell invasion assay detected cell invasion ability. Wound healing assay assessed cell migration ability. Xenograft tumor was established to evaluate tumor growth. Quantitative real-time polymerase chain reaction (qRT-PCR), Western blot and immunohistochemistry were performed to determine mRNA or protein levels. RESULTS: PRR11 was elevated in CRC. PRR11 silencing suppressed CRC cell proliferation, invasion, and migration ability. Besides, PRR11 silencing inhibited EGFR/ ERK/ AKT pathway via restraining Collagen triple helix repeat containing-1 (CTHRC1) expression. Furthermore, knockdown of PRR11 suppressed CRC tumor growth in vivo. CONCLUSION: PRR11 was highly expressed in CRC. PRR11 silencing suppressed proliferation, invasion, migration, and tumor growth of CRC through inhibiting the EGFR/ERK/AKT pathway via restraining CTHRC1 expression. PRR11 may be a valuable therapeutic target for CRC.

Prognostic significance of autophagy-related proteins expression in resected human gastric adenocarcinoma.

Gastric adenocarcinoma (GC) is one of the most common malignancies in the world and one of the most frequent causes of cancer-related death. Autophagy is a highly regulated catabolic pathway responsible for the degradation of long-lived proteins and damaged intracellular organelles. However, the mechanism and guiding significance of autophagy in the development and progression of GC have remained to be elucidated. This study aimed to explore the clinicopathological significances and prognostic values of autophagy-related proteins AMBRA1 and Beclin-1 in GC. Quantum dots based immunofluorescence histochemistry (QDs-IHC) was performed to observe the expression of AMBRA1 and Beclin-1 proteins in the tissue microarrays including 163 specimens of GC and 20 noncancerous gastric tissues. Simultaneously, AMBRA1 and Beclin-1 proteins were detected by Western blotting in the 10 fresh GC and corresponding normal gastric tissues. The results showed that the expression levels of both AMBRA1 and Beclin-1 proteins were higher in GC tissues than in noncancerous gastric tissues by QDs-IHC and Western blotting (P<0.05). High AMBRA1 expression was detected in 90 of 163 (55.2%) GCs and high Beclin-1 expression was detected in 83 of 163 (50.9%) GCs. High AMBRA1 expression was closely related to depth of invasion, and lymph nodes metastasis (P<0.05). High expression of Beclin-1 protein was correlated with tumor grade (P<0.05). Positive correlation was observed between AMBRA1 and Beclin-1. Survival analysis indicated the high expression of AMBRA1 and Beclin- 1 was an independent factor in predicting poor overall survival (OS) of GC patients. These findings suggest the high expression of AMBRA1 and Beclin-1 proteins is significantly correlated with GC progression. High AMBRA1 and Beclin-1 expression heralds worse outcome of GC patients, suggesting a novel candidate prognostic marker and a therapeutic target for GC.

Prognostic Significance of Autophagy-Related Proteins Expression in Resected Human Gastric Adenocarcinoma / 华中科技大学学报（医学）（英德文版）

Gastric adenocarcinoma (GC) is one of the most common malignancies in the world and one of the most frequent causes of cancer-related death.Autophagy is a highly regulated catabolic pathway responsible for the degradation of long-lived proteins and damaged intracellular organelles.However,the mechanism and guiding significance of autophagy in the development and progression of GC have remained to be elucidated.This study aimed to explore the clinicopathological significances and prognostic values of autophagy-related proteins AMBRA1 and Beclin-1 in GC.Quantum dots based immunofluorescence histochemistry (QDs-IHC) was performed to observe the expression of AMBRA1 and Beclin-1 proteins in the tissue rmicroarrays including 163 specimens of GC and 20 noncancerous gastric tissues.Simultaneously,AMBRA1 and Beclin-1 proteins were detected by Western blotting in the 10 fresh GC and corresponding normal gastric tissues.The results showed that the expression levels of both AMBRA1 and Beclin-1 proteins were higher in GC tissues than in noncancerous gastric tissues by QDs-IHC and Western blotting (P＜0.05).High AMBRA1 expression was detected in 90 of 163 (55.2％) GCs and high Beclin-1 expression was detected in 83 of 163 (50.9％) GCs.High AMBRA1 expression was closely related to depth of invasion,and lymph nodes metastasis (P＜0.05).High expression of Beclin-1 protein was correlated with tumor grade (P＜0.05).Positive correlation was observed between AMBRA1 and Beclin-1.Survival analysis indicated the high expression of AMBRA1 and Beclin-1 was an independent factor in predicting poor overall survival (OS) of GC patients.These findings suggest the high expression of AMBRA1 and Beclin-1 proteins is significantly correlated with GC progression.High AMBRA1 and Beclin-1 expression heralds worse outcome of GC patients,suggesting a novel candidate prognostic marker and a therapeutic target for GC.

The amino acid sensor GCN2 controls gut inflammation by inhibiting inflammasome activation.

The integrated stress response (ISR) is a homeostatic mechanism by which eukaryotic cells sense and respond to stress-inducing signals, such as amino acid starvation. General controlled non-repressed (GCN2) kinase is a key orchestrator of the ISR, and modulates protein synthesis in response to amino acid starvation. Here we demonstrate in mice that GCN2 controls intestinal inflammation by suppressing inflammasome activation. Enhanced activation of ISR was observed in intestinal antigen presenting cells (APCs) and epithelial cells during amino acid starvation, or intestinal inflammation. Genetic deletion of Gcn2 (also known as Eif2ka4) in CD11c(+) APCs or intestinal epithelial cells resulted in enhanced intestinal inflammation and T helper 17 cell (TH17) responses, owing to enhanced inflammasome activation and interleukin (IL)-1ß production. This was caused by reduced autophagy in Gcn2(-/-) intestinal APCs and epithelial cells, leading to increased reactive oxygen species (ROS), a potent activator of inflammasomes. Thus, conditional ablation of Atg5 or Atg7 in intestinal APCs resulted in enhanced ROS and TH17 responses. Furthermore, in vivo blockade of ROS and IL-1ß resulted in inhibition of TH17 responses and reduced inflammation in Gcn2(-/-) mice. Importantly, acute amino acid starvation suppressed intestinal inflammation via a mechanism dependent on GCN2. These results reveal a mechanism that couples amino acid sensing with control of intestinal inflammation via GCN2.