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Background Accumulating evidence has shown that protein tyrosine phosphatases (PTPs) are involved in regulating the transduction of many signaling pathways and play important roles in modulating the progression of some cancers, but the functions of PTPs in cancers have not been well elucidated until now. Here, we aimed to identify the roles of protein tyrosine phosphatase nonreceptor type 9 (PTPN9), a cytoplasmic PTP, in the development of colorectal cancer and elucidate the regulatory mechanism involved. Materials and methods Cell viability assessment, colony formation assay, caspase-3 and caspase-9 activity assay, real-time PCR, and Western blot analysis were applied. Results Our results showed that PTPN9 expression was frequently downregulated in colorectal cancer tissues compared with adjacent normal tissues. Overexpression of PTPN9 mitigated cell growth and colony formation and induced cell apoptosis in colorectal cancer. Conversely, PTPN9 knockdown promoted cell growth and survival. Moreover, PTPN9 negatively regulated the activation of Stat3 and depressed its nuclear translocation in colorectal cancer. The effects of PTPN9 knockdown on cell apoptosis were attenuated by inhibition of the Stat3 pathway. Conclusion These results indicate that PTPN9 inhibits cell growth and survival by repressing the activation of Stat3 in colorectal cancer, which suggests an important underlying mechanism of regulating cell growth and provides a novel candidate therapeutic target for colorectal cancer.

BackgroundUnfolded protein response (UPR)-mediated tumor-promoting functions have been identified in multiple cancers, and this study focused on investigating the role and molecular mechanisms of UPR in modulating gastric cancer (GC) pathogenesis.MethodsThe bioinformatics analysis was performed to examine the expression status of cancer associated genes in patients with stomach adenocarcinoma (STAD) and predict the targeting sites of miR-224-5p with LncRNA MIR503HG and TUSC3. Genes expressions were quantified by Real-Time qPCR, Western Blot and immunohistochemistry (IHC). Cell proliferation, viability, apoptosis and mobility were evaluated by MTT assay, trypan blue staining assay, flow cytometer and transwell assay, respectively. The binding sites were validated by dual-luciferase reporter gene system assay.ResultsLncRNA MIR503HG and TUSC3 were downregulated, but miR-224-5p was upregulated in GC tissues and cells, in contrast with their normal counterparts. Further gain- and loss-of-function experiments validated that the malignant phenotypes in GC cells, including cell proliferation, invasion, epithelial-mesenchymal transition (EMT) and tumorigenesis, were negatively regulated by LncRNA MIR503HG. Mechanistically, LncRNA MIR503HG upregulated TUSC3 in GC cells through sponging miR-224-5p, resulting in the repression of GC progression. Finally, we validated that knock-down of ATF6, but not other two branches of UPR (PERK1 and IRE1), partially rescued cell proliferation and EMT in the GC cells with LncRNA MIR503HG overexpression.ConclusionsTargeting the LncRNA MIR503HG/miR-224-5p/TUSC3 signaling cascade suppressed ATF6-mediated UPR, resulting in the blockage of GC development.

Colorectal cancer (CRC) is a gastrointestinal malignancy originating from either the colon or the rectum. A growing number of researches prove that the unfolded protein response (UPR) is closely related to the occurrence and progression of colorectal cancer. The UPR has three canonical endoplasmic reticulum (ER) transmembrane protein sensors: inositol requiring kinase 1 (IRE1), pancreatic ER eIF2α kinase (PERK), and activating transcription factor 6 (ATF6). Each of the three pathways is closely associated with CRC development. The three pathways are relatively independent as well as interrelated. Under ER stress, the activated UPR boosts the protein folding capacity to maximize cell adaptation and survival, whereas sustained or excessive ER triggers cell apoptosis conversely. The UPR involves different stages of CRC pathogenesis, promotes or hinders the progression of CRC, and will pave the way for novel therapeutic and diagnostic approaches. Meanwhile, the correlation between different signal branches in UPR and the switch between the adaptation and apoptosis pathways still need to be further investigated in the future.

Dihydromethysticin (DHM), a natural compound derived from Kava, has been reported to be effective against mental disorders and some malignant tumors. However, little is known about the inhibitory effect of DHM on colorectal cancer (CRC). First, we examined the impact of DHM on human colon cancer cell lines, which demonstrated that DHM inhibits proliferation, migration, and invasion and promotes apoptosis and cell cycle arrest in colon cancer cells in vitro. Using small hairpin RNA, we inhibited nucleotide-oligomerization domain-like receptor subfamily C3 (NLRC3)/phosphoinositide 3-kinase (PI3K) pathway to elucidate the partial signaling of DHM-mediated tumor suppression. Additionally, using an ectopic human CRC model, we verified whether DHM inhibits tumor growth and angiogenesis via the NLRC3/PI3K pathway in vivo. Overall, DHM showed an inhibitory effect on CRC by altering cell proliferation, migration, invasion, apoptosis, cell cycle, and angiogenesis, possibly via the NLRC3/PI3K pathway. Thus, DHM may be a promising candidate for CRC therapy.

Scope Hydroxytyrosol (HT), a main phenolic compound in olive oil, has been proved to be a potent antioxidant and has beneficial effects on health. However, the effect of HT on oxidative liver damage, as seen in ischemia/reperfusion (I/R) injury, is unknown. Here, we examined whether HT could protect liver against I/R injury. Methods and results By using a mouse model, we found that HT administration protects against hepatic I/R injury, as indicated by the decreased levels of serum aminotransferase and less parenchymal necrosis and apoptosis. Serum levels of tumor necrosis factor-α, interleukin-6, macrophage inflammatory protein 2, as well as reactive oxygen species (ROS) content in liver tissues, were all decreased by HT, the latter correlated with the reduction of hepatic malondialdehyde (an index of oxidative stress) content and increased activities and expressions of liver antioxidant enzymes superoxide dismutase and catalase. The protective effect was also seen in isolated hepatocytes anoxia/reoxygenation assay. Conclusion HT exerts protective effects against hepatic I/R injury in mice, which might be associated with its anti-oxidative, anti-inflammatory, and anti-apoptotic properties. HT may be an effective hepatoprotective agent and a promising candidate for the treatment of liver I/R injury.

Background Most of the reports on the prognostic indicators of patients with pancreatic adenocarcinoma are from developed countries. The present study focused on the prognostic indicators of Chinese patients with pancreatic adenocarcinoma. Methods A total of 300 patients with pancreatic adenocarcinoma who had undergone curative resection were included. The resection and R0/R1 resection rates for adenocarcinomas from different parts of the pancreas were calculated and clinical characteristics were analyzed. Results In 3427 patients diagnosed with pancreatic adenocarcinomas, only 300 (8.8%) were eligible for radical resection. The total median survival of these patients was 19 months, and their 1-, 3-, and 5-year survival rates were 72.5%, 28.0% and 23.4%, respectively. The prognostic factors included socioeconomic status, smoking history, symptoms, high blood glucose, and various tumor characteristics, including perineural and vascular invasion, lymph node metastases, and CA19-9 levels before and after operation. Operation-associated prognostic indicators included operation time, blood loss and transfusions, pancreatic fistula, and complications. Independent predictors of mortality included poor socioeconomic status, smoking history, symptoms, CA19-9, perineural invasion and lymph node metastasis, grade of fistula and complications. Patient survival was not correlated with either resection margin or adjuvant chemotherapy in multivariate analysis. Conclusions The survival rates of patients with curative resection for pancreatic adenocarcinoma in China are close to those in developed countries, but curative resection rate is far below. Socioeconomic status, symptoms, and CA19-9 are the three most prominent prognostic factors, which are helpful in patient selection and perioperative care.

Cholangiocarcinoma (CCA) is a notoriously lethal tumor mostly due to the de novo or acquired resistance to traditional chemotherapy besides gemcitabine and, therefore, an increasing need for effective strategies to prevent and treat the poor prognosis of this tumor is required. Thymoquinone (TQ), a hopeful natural product derived from black cumin (Nigella sativa) has shown considerable antineoplastic properties. Whether TQ exerts antitumor effects on CCA cells in vitro and in vivo remains unknown. Examinations of cell viability assay, detection of cell cycle and apoptosis, electrophoretic mobility shift assay (EMSA), western blotting and immunohistochemistry were used in the present study. We demonstrated that TQ inhibited the growth of human CCA cell lines (TFK-1 and HuCCT1) in a dose- and time-dependent manner. Firstly, our results provided evidence that TQ not only inhibits the proliferation of CCA cells, induces cell cycle arrest and prompts cell apoptotic effect in vitro, but it also exhibits inhibitory effects of tumor growth and angiogenesis in vivo. The responsible mechanism is at least partially due to TQ inhibiting the growth of CCA cell lines induced by downregulation of PI3K/Akt and NF-κB and regulated gene products, including p-AKT, p65, XIAP, Bcl-2, COX-2, VEGF. Taken together, these results provide strong evidence of our hypothesis that TQ alone presents a promising therapeutic regimen for the treatment of CCA cells with better efficiency.

The spleen is a crucial lymphoid organ. It is involved in the recruitment of various immunocytes to their correct locations using specific chemokines, but little is known concerning the role of type-I interferon (IFN) in the regulation of chemokines. In this study, we first used protein microarrays to assess the expression of keratinocyte-derived chemokine (KC) and lipopolysaccharide-induced CXC chemokine (LIX) in murine spleens. Both expressions were smoothly enhanced by IFN-α pretreatment after LPS injection. Then, we focused on the IFN-α regulation of KC, LIX, and their target cells, neutrophils, using an IFN-α neutralizing antibody and fludarabine (specific signal transducers and activators of transcription 1 - STAT1 inhibitor). Next, LPS was found to attenuate the production of KC and LIX in spleen. Even the elevated production of chemokines caused by exogenous IFN-α was found to be attenuated by fludarabine pretreatment. We later determined that the marginal zone and red pulp are the main sites of KC and LIX production. Last, we determined that the number of neutrophils was slightly increased by IFN-α treatment and diminished by IFN-α neutralization or fludarabine treatment. Further, the elevated neutrophils due to exogenous IFN-α were partially reversed by fludarabine pretreatment. In this way, these results indicate that IFN-α facilitates KC and LIX expression in mouse spleens after an LPS challenge. This effect was found to be mainly dependent upon the activation of STAT1, it may be involved in the recruitment of neutrophils to the spleen for the clearance of pathogens.

Hydrogen sulphide (H 2S) exerts a protective effect in hepatic ischemia-reperfusion (I/R) injury. However, the exact mechanism of H 2S action remains largely unknown. This study was designed to investigate the role of the PtdIns3K-AKT1 pathways and autophagy in the protective effect of H 2S against hepatic I/R injury. Primary cultured mouse hepatocytes and livers with or without NaHS (a donor of H 2S) preconditioning were exposed to anoxia/reoxygenation (A/R) and I/R, respectively. In certain groups, they were also pretreated with LY294002 (AKT1-specific inhibitor), 3-methyladenine (3MA, autophagy inhibitor) or rapamycin (autophagy enhancer), alone or simultaneously. Cell viability, expression of P-AKT1, T-AKT1, LC3 and BECN1 were examined. The severity of liver injury was measured by the levels of serum aminotransferase and inflammatory cytokine, apoptosis and histological examination. GFP-LC3 redistribution and transmission electron microscopy were used to test the activity of autophagy. H 2S preconditioning activated PtdIns3K-AKT1 signaling in hepatocytes. LY294002 could abolish the AKT1 activation and attenuate the protective effect of H 2S on hepatocytes A/R and hepatic I/R injuries. H 2S suppressed hepatic autophagy in vitro and in vivo. Further reducing autophagy by 3MA also diminished the protective effect of H 2S, while rapamycin could reverse the autophagy inhibitory effect and enhance the protective effect of H 2S against hepatocytes A/R and hepatic I/R injuries, consequently. Taken together, H 2S protects against hepatocytic A/R and hepatic I/R injuries, at least in part, through AKT1 activation but not autophagy. An autophagy agonist could be applied to potentiate this hepatoprotective effect by reversing the autophagy inhibition of H 2S.