Expression of CXCL12-CXCR4/CXCR7 chemokines in splenic fibrosis of cirrhotic spleen and its therapeutic significance.

Introduction: To investigate the expression and treatment of chemokine CXCL12 and its receptor CXCR4/CXCR7. Methods: The liver cirrhosis hypersplenism model of rats was made with CCL4, and then was detected by immunohistochemistry, Western blot and qRT-PCR. Results: The area of spleen fibrosis in the model group was significantly larger than that in the control group (p < 0.01), and the expression of CXCL12, CXCR4 and CXCR7 in the model group was significantly higher than that in the control group (p < 0.01). Conclusions: CXCL12-CXCR4/CXCR7 is abnormally high in splenic fibrosis, and blocking its high expression can slow down the occurrence of hypersplenism.

Coagulation Dysfunction in Patients with Liver Cirrhosis and Splenomegaly and Its Countermeasures: A Retrospective Study of 1522 Patients.

Objective: Patients with cirrhosis and splenomegaly often have coagulation dysfunction which affects treatment and prognosis. This study explores the status, grading, and treatment strategies of coagulation dysfunction in patients with liver cirrhosis and splenomegaly. Methods: A retrospective cohort study was conducted on the clinical data on consecutive patients with cirrhosis and splenomegaly treated at Hainan General Hospital, China, from January 2000 to December 2020. Starting research in January 2022. Results: Among 1522 patients included into this study, 297 (19.5%) patients had normal results in all five coagulation tests (prothrombin time, prothrombin activity, activated partial thromboplastin time, thrombin time, and fibrinogen), and 1225 (80.5%) had coagulation dysfunction in at least one of these tests. There were significant differences (P < 0.05) in treatment efficacy on these patients for three of these five coagulation tests, with the exception of prothrombin activity and thrombin time. When coagulation dysfunction was classified into grades I, II, and III based on scores from the three significant coagulation tests, prothrombin time, activated partial thromboplastin time, and fibrinogen, significant differences in surgical outcomes were found among the three grades of coagulation dysfunction and between grades I and III (P < 0.05). The operative mortality rate in patients with grade III in treating liver cancer, portal hypersplenism, and/or splenomegaly was 6.5%. There was no significant difference between patients with grades I and II (P > 0.05). Conclusions: Approximately, 80% of patients with liver cirrhosis and splenomegaly had coagulation dysfunction. Surgery is feasible for grade I and II patients. For grade III patients, nonsurgical treatment should be given first, and surgery should only be considered when the coagulation function returns to normal or near-normal levels after treatment. This trial is registered with MR-46-22-009299.

circIFT80 Functions as a ceRNA for miR-142, miR-568, and miR-634 and Promotes the Progression of Colorectal Cancer by Targeting ß-Catenin.

Colorectal cancer (CRC) is the third most common form of malignant tumor and is characterized by high rates of proliferation and metastases. Circular RNAs (circRNAs) are a form of noncoding and closed loop RNA molecules and play vital roles in the progression of various types of cancer in humans. Here, we used circRNA microarray sequencing technology to analyze the different circRNAs between CRC tissues and normal tissues and explore the role of circIFT80 in progression of colorectal cancer. In this present study, we found that circIFT80 was abnormally overexpression in colorectal cancer tissues and tumor cells. While knockout circIFT80 in HT29 cell or SW480 cells, the proliferation, and migration of the cells were inhibited, the cell cycle was arrested in G2/M phase, and the cell apoptosis was increased. And then, we found circIFT80-positive correlation with CTNNB1 (ß-catenin) by sponging miR-142, miR-568, and miR-634 upregulated the gene expression. These miRNAs which targeted ß-catenin mRNA were confirmed by dual-luciferase reporter system and RNA-pulldown. In addition, xenograft tumor experiments showed that circIFT80 accelerated the tumorigenesis of CRC in vivo. In conclusion, our work reveals the impacts of circIFT80 as ceRNA in the progression of CRC, by which sponging miR-142, miR-568, and miR-634 enhanced the expression levels of ß-catenin and activation Wnt/ß-catenin pathway. Collectively, our data indicate that circIFT80 serves as an oncogene in CRC and represents a novel candidate for diagnosis and treatment.

Antibody and complement levels in patients with hypersplenism associated with cirrhotic portal hypertension and therapeutic principles.

BACKGROUND: Hypersplenism associated with cirrhotic portal hypertension is a common condition often resulting from hepatitis B-related cirrhosis. However, the levels of immunoglobulin (Ig) and complement in patients with hypersplenism associated with cirrhotic portal hypertension remain unclear. This study was undertaken to determine the levels of Ig and complement in these patients, the relationship between these levels and Child-Pugh class and their clinical significance. AIM: To investigate the antibody (Ig) and complement levels in patients with hypersplenism associated with cirrhotic portal hypertension and their clinical significance. METHODS: Clinical data of 119 patients with hypersplenism associated with cirrhotic portal hypertension were statistically analyzed and compared with those of 128 control patients. RESULTS: IgA and IgG levels in patients with hypersplenism were significantly higher than controls (P < 0.001). There was no significant difference in IgM between the two groups (P = 0.109). C3 and C4 levels in patients with hypersplenism were significantly lower than controls (P < 0.001). As liver function decreased, IgA and IgG levels increased (P < 0.001), and C3 and C4 levels decreased (P < 0.001). CONCLUSION: Patients with hypersplenism associated with cirrhotic portal hypertension have significantly higher antibody (IgA and IgG) levels and significantly lower complement (C3 and C4) levels, which are both related to liver damage. Clinically, the administration of anti-hepatitis virus agents and protection of liver function should be strengthened.

Impact of total splenectomy on peripheral lymphocytes and their subsets in patients with hypersplenism associated with cirrhotic portal hypertension.

To study the impact of total splenectomy (TS) on peripheral lymphocytes and their subsets in patients with hypersplenism associated with cirrhotic portal hypertension (CPH). We studied 102 consecutive patients who received TS from January 2008 to January 2020 due to CPH-related hypersplenism. A similar number of healthy individuals are used as healthy controls (HC). The total lymphocyte counts and their percentages of B lymphocytes, total T lymphocytes (cluster of differentiation (CD)3+) and their subsets (CD4+, CD8+), and natural killer (NK) cells in preoperative peripheral blood samples in hypersplenism patients were significantly lower than that of the HCs (both P < 0.05). The total lymphocyte counts and percentages of B lymphocytes in peripheral blood were significantly increased 1 week and 1 month after TS when compared with the pre-TS values (P < 0.05). There was no significant difference in the percentages of NK cells before or after surgery (P > 0.05). However, the percentages of CD3+ cells was significantly higher 1 month after than before surgery (P < 0.001). The percentages of CD4+, and CD8+ T lymphocytes were significantly lower 1 week after surgery (P < 0.05), but they were significantly higher 1 month after surgery (P < 0.01). The CD4+:CD8+ ratio was not significantly different from those before surgery, and 1 week or 1 month after surgery (P > 0.05). Patients with hypersplenism associated with CPH were significantly immunosuppressed preoperatively. After TS, the total lymphocyte count and percentages of B lymphocytes, and total T lymphocytes and their subsets increased significantly, resulting in improved immune functions.

Etiological classification and treatment strategies for secondary bile duct dilatation.

Secondary intra- and extrahepatic bile duct dilatation is a very common condition that can be caused by several diseases. However, it has been rarely discussed in the specialized literature. Moreover, no distinct etiology can be determined in some cases, which hampers the diagnosis and treatment. Here, we discuss the etiological classification and treatment strategies of secondary intra- and extrahepatic bile duct dilatation based on an extensive literature review, as well as our experimental research and clinical experience. The etiology of secondary intra- and extrahepatic bile duct dilatation can be classified in different ways. From a clinicopathological perspective, it can be classified into obstruction-, lesion-, and compression-induced dilatation. Treatment varies depending on the cause. For example, endoscopic dilation or stenting is used for biliary strictures, laparoscopic choledochectomy for stone removal, and resection for cholangiocarcinoma.

Investigation into imbalance of Th1/Th2 cells in cirrhotic, hypersplenic rats.

OBJECTIVES: To evaluate the Th1/Th2 cell profile in spleens of cirrhotic and hypersplenic rats by investigating the expression of Th1-associated chemokine receptors CXCR3, CCR5 and Th2-associated chemokine receptor CCR3. METHODS: Experimental liver cirrhosis and hypersplenism were induced in rats by the intragastric administration of carbon tetrachloride (CCl4; 40% solution [0.3 ml/100g, twice/week for 8 weeks]) and confirmed by pathology and hemogram. Presence of the three chemokine receptors was investigated by real-time polymerase chain reaction (RT-PCR), immunohistochemical staining, and western blot analysis. RESULTS: By comparison with control animals (n=10), RT-PCR demonstrated that CXCR3 and CCR5-mRNA levels were significantly elevated in the hypersplenic rats (n=26) and CCR3-mRNA levels were lower. Immunohistochemical staining showed that by comparison with controls, the mean density of the Th1-associated CXCR3 and CCR5 receptors was significantly increased but there was no difference between groups in Th2-associated CCR3 receptors. Western blot analysis showed that by comparison with controls, hypersplenic rats had higher levels of CXCR3 and CCR5 protein but lower levels of CCR3 protein. CONCLUSIONS: The abnormal expression of Th1-associated chemokine receptors in spleens of rats with cirrhosis and hypersplenism induced by CCL4 suggests that a functional imbalance between Th1/Th2 cells may play a role in the pathogenesis of hypersplenism.

Spontaneous remission of obstructive jaundice in rats: Selection of experimental models.

The aim of the present study was to evaluate the prevalence and causes of spontaneous remission of obstructive jaundice in rats. Healthy male and female Wistar rats (180-220 g) were randomly assigned to receive common bile duct ligation (CBDL) and transection (group A), CBDL only (group B), or CBD dissection without ligation or transection (control group C; n=36 in each group). There was a difference in eye and skin jaundice prevalence between groups A and B from 14 days after surgery. The level of total bilirubin (TB) did not continue to increase in group A and began to decrease in the majority of rats in group B (P<0.05 vs. group B). At day 21 after surgery, the TB level returned to normal in group B and no significant difference was observed compared with group C. At day 21 after surgery, significant dilatation of bile ducts above the ligature was observed in group A following cholangiography with 38% meglumine diatrizoate and this contrast agent did not spread to other sites. Slight dilatation of the proximal bile ducts was observed in group B and the contrast agent entered the intestinal lumen through the omental ducts adhering to the porta hepatis. After 14 days of surgery, there were 36 rats in group A and B, and 17 rats exhibited spontaneous regression of jaundice. Overall, 47.2% (17/36) of rats experienced spontaneous remission of obstructive jaundice, 82.4% (14/17) of which underwent ligation only. The spontaneous remission of jaundice may have been caused by shunting through very small bile ducts or omental ducts adhering to the porta hepatis. If a model of biliary obstruction is to be established in future research, a model of CBDL and transection is preferable. In this case, jaundice reduction surgery should be performed 14 days after establishment of the model.

Distribution characteristics of cells in splenomegaly due to hepatitis B-related cirrhotic portal hypertension and their clinical importance.

Objectives To investigate peripheral cytopenia in patients with splenomegaly due to hepatitis B-related cirrhotic portal hypertension (HBRCPH) by comparing blood cell counts from enlarged spleens with peripheral blood. Methods This prospective study involved patients undergoing splenectomy at the Nangfang Hospital from June 2013 to December 2015. Blood cell counts from peripheral blood were compared with those from splenic blood taken during splenectomies. Results Clinical data were available from 30 patients. White blood cell (WBC), red blood cell (RBC) and platelet counts were statistically significantly lower in peripheral blood compared with splenic blood. After splenectomy, peripheral blood cell counts increased significantly compared with pre-operative levels. Platelet and WBC counts in the lower spleen were significantly higher than those in the porta lienis (middle segment) and upper spleen. Conclusions In patients with splenomegaly due to HBRCPH, the counts of three blood cell lineages were significantly higher in the spleen than in peripheral blood. Splenectomy can aid the return of peripheral blood cell counts to normal levels. The most significant retention of platelets and WBCs occurred in the lower spleen which may be useful information for surgeons performing partial splenectomies.

A Comprehensive Model for Predicting Recurrence and Survival in Cases of Chinese Postoperative Invasive Breast Cancer

We investigated relationships between clinical pathologic data, molecular biomarkers and prognosis of invasive breast cancer based on a Chinese population. Immunohistochemistry (IHC) was used to assess the status of ER, PR, HER-2 and Ki-67, with fluorescence in situ hybridization (FISH) performed to further confirm HER-2 positivity with an equivocal result (IHC 2+). Subsequently, Kaplan-Meier univariate and multivariate COX regression analyses of ER, PR, HER-2, Ki-67, clinical features, therapeutic status and follow-up data were performed according to the establishment principle of the Nottingham prognostic index (NPI). From this study, age, tumor size, lymph node status, ER, HER-2, Ki-67 status were found to be associated with prognosis. Eventually, a prognostic model of (PI= (1.5×age) - size + (0.1×lymph node status) - (0.5×ER) + (2×HER-2) - (0.2×Ki-67)) was established with 288 randomly selected patients and verified with another 100 cases with invasive breast cancer. Pearson correlation analysis demonstrated a significant positive correlation index of 0.376 (P=0.012<0.05) between the prognostic index (PI) and actual prognosis. Remarkably, the consistency with the model predicted recurrence was 93% in the validation set. Therefore, it appears feasible to predict the prognosis of individuals with invasive breast cancer and to determine optimal therapeutic strategy with this model.

Causes of peripheral cytopenia in hepatitic cirrhosis and portal hypertensive splenomegaly.

The clinical data of 183 patients with hepatitic cirrhosis and portal hypertensive splenomegaly complicated by peripheral cytopenia were retrospectively analyzed to investigate the causes of peripheral cytopenia, as well as the proportion of the causes in these patients. All patients underwent splenectomy. Before operation, these patients had one or more types of peripheral cytopenia (cumulative cytopenia: 390 patient-times). After splenectomy, blood counts in 79.2% (309/390) returned to normal, while in 15.9% (62/390) they increased but failed to reach to normal levels, and in 4.9% (19/390) they became lower than before the operations. For the last group of patients ( n = 19), long-term follow-up showed that blood counts returned to normal in five patients. In other words, in 80.5% [(309 + 5)/390 or 314/390] of patient-times, the peripheral cytopenia was due to hypersplenism, in 15.9% it was due to a combination of factors, and in 3.6% [14/390] it had nothing to do with the hypersplenism. Thus, hypersplenism is a major cause, but not the only cause, of peripheral cytopenia in patients with hepatic cirrhosis and portal hypertensive splenomegaly, and splenectormy is an effective treatment for these patients. Impact statement For a long time, the development of peripheral cytopenias as a complication to cirrhotic portal hypertension has been attributed to hypersplenism; however, this has never been fully demonstrated. Dameshek summarized that hypersplenism should be diagnosed by the presence of four conditions: (a) mono- or multi-lineage peripheral cytopenias; (b) compensatory hyperplasia of bone marrow; (c) splenomegaly; and (d) correction of cytopenias after splenectomy. We retrospectively analyzed the clinical data from 183 surgical patients, and found that 80.5% of peripheral cytopenias was caused by hypersplenism, 16% by a combination of factors, and 3.5% by other factors unrelated to hypersplenism. As the first quantitative findings in this field, our results verify that hypersplenism is a major, but not exclusive, cause of peripheral cytopenias, and provides important clinical evidence for investigating the cause of peripheral cytopenias.

Hypersplenism: History and current status.

Hypersplenism is a common disorder characterized by an enlarged spleen which causes rapid and premature destruction of blood cells. This review summarizes the history of hypersplenism, discuss its classification and pathogenesis, and examines its diagnosis and treatment options. We performed a comprehensive literature search using PubMed, Web of Knowledge and the China National Knowledge Infrastructure (CNKI) database, reviewed hypersplenism-related articles and summarized the major findings. According to its etiological causes, hypersplenism is characterized by splenomegaly and peripheral cytopenias. It can be classified into three categories: i) primary hypersplenism; ii) secondary hypersplenism; and iii) occult hypersplenism. A number of mechanisms causing hypersplenism have been identified, and mainly involve retention in the spleen, phagocytosis, and autoimmunity. Treatment options for hypersplenism include etiological treatment, non-surgical treatment, total splenectomy and liver transplantation. In any case, treatment should be individualized for each patient.

Hydrogen peroxide mediates hyperglycemia-induced invasive activity via ERK and p38 MAPK in human pancreatic cancer.

Diabetes mellitus and pancreatic cancer are intimately related, as approximately 85% of pancreatic cancer patients suffer from glucose intolerance or even diabetes. In this study, we evaluate the underlying mechanism by which hyperglycemia modulates the invasive potential of cancer cells and contributes to their enhanced metastatic behavior. Here we show that hyperglycemia increases the hydrogen peroxide (H2O2) concentration through up-regulation of manganese superoxide dismutase (SOD2) expression, which further activates the ERK and p38 MAPK pathways, as well as the transcription factors NF-κB and AP-1, in a time-dependent manner. The invasion of pancreatic cancer cells resulting from the activation of the H2O2/MAPK axis under high glucose conditions is effectively inhibited by PD 98059 (ERK inhibitor), SB 203580 (p38 MAPK inhibitor), polyethylene glycol-conjugated catalase (PEG-CAT), or the siRNA specific to SOD2. In addition, streptozotocin-treated diabetic nude mice exhibit a stronger tumor invasive ability in renal capsule xenografts which could be suppressed by PEG-CAT treatment. Furthermore, the integrated optical density (IOD) of SOD2 and uPA stainings is higher in the tumor tissues of pancreatic cancer patients with diabetes compared with pancreatic cancer patients with euglycemia. Taken together, our results demonstrate that hyperglycemia enhances cell invasive ability through the SOD2/H2O2/MAPK axis in human pancreatic cancer. Thus, SOD2/H2O2/MAPK axis may represent a promising therapeutic target for pancreatic cancer patients combined with diabetes mellitus.

Grading of peripheral cytopenias caused by nonalcoholic cirrhotic portal hypertension and its clinical significance.

This study investigates peripheral cytopenias in patients with splenomegaly caused by nonalcoholic cirrhotic portal hypertension. Data from 330 splenomegaly cases caused by nonalcoholic cirrhotic portal hypertension were collected and analyzed using univariate and multivariate analysis. The cytopenias were scored and graded according to the F value of the multiple linear regression equation. Based on the severity of thrombocytopenia, cytopenia was graded as mild, moderate, or severe, and determined by a score of <2 points, 2-3 points, and >3 points. 30 % of the patients had monolineage cytopenias, 35.8 % had bilineage cytopenias, and 34.2 % had trilineage cytopenias. All patients were treated surgically. In the univariate analysis, the severity of erythropenia was different in the surgical outcome when compared to the intra-group (P < 0.05). In the multivariate analysis, thrombocytopenia was different in the surgical outcomes when compared with leukopenia and erythropenia (P < 0.05). There was a significant difference in surgical outcomes between the three grades (mild, moderate, and severe) of cytopenia (P < 0.05). Peripheral cytopenias have a significant impact on the clinical outcomes. The more severe the cytopenias, the worse the surgical outcomes are. Thrombocytopenia is a major factor influencing surgical outcomes. The thrombocytopenia-based three-level grading of cytopenias provides a basis for analyzing individual cases, planning treatment, and assessing prognosis in clinical practice.

Hyperglycemia regulates TXNIP/TRX/ROS axis via p38 MAPK and ERK pathways in pancreatic cancer.

Approximately 85% of pancreatic cancer patients suffer from glucose intolerance or even diabetes because high glucose levels can contribute to oxidative stress which promotes tumor development. As one of the reactive oxygen species (ROS)-regulating factors, thioredoxin-interacting protein (TXNIP), is involved in the maintenance of thioredoxin (TRX)-mediated redox regulation. In this study, we demonstrated that high glucose levels increased the expression of TXNIP in time- and concentration-dependent manners and modulated the activity of TRX and ROS production in pancreatic cancer cells, BxPC-3 and Panc-1. We also found that glucose activated both p38 MAPK and ERK pathways and inhibitors of these pathways impaired the TXNIP/TRX/ROS axis. Knockdown of TXNIP restored TRX activity and decreased ROS production under high glucose conditions. Moreover, we observed that the integrated optical density (IOD) of TXNIP staining as well as the protein and mRNA expression levels of TXNIP were higher in the tumor tissues of pancreatic cancer patients with diabetes. Taken together, these results indicate that hyperglycemia-induced TXNIP expression is involved in diabetes-mediated oxidative stress in pancreatic cancer via p38 MAPK and ERK pathways.

Clinical study on the relationship between hematocytopenia and splenomegaly caused by cirrhotic portal hypertension.

This clinical study was designed to evaluate the presence of hematocytopenia in patients with splenomegaly caused by non-alcoholic cirrhotic portal hypertension. For this purpose, we randomly selected 358 patients with splenomegaly caused by non-alcoholic cirrhotic portal hypertension and admitted to the clinical data in our hospital between January 1991 and June 2009. Among these 358 patients, 322 patients (90.0 %) showed hematocytopenia, including multi-hemocyte decrease in 206 patients (i.e., 89 patients with a decrease in white blood cell count (WBC) + red blood cell count (RBC) + platelets count (PLT)); 52 patients with WBC + PLT decrease; 29 patients with RBC + PLT decrease; and 36 patients with WBC + RBC decrease) and single-hemocyte decrease in 116 patients (i.e., 31 cases with single PLT decrease; 29 cases with single WBC decrease; and 56 patients with single RBC decrease). After splenectomy, 36 patients (10.0 %) with hematocytopenia presented a statistical improvement of blood cell to normal level (P < 0.05), while 32 patients did not have any change as compared to pre-operative one (P > 0.05). It has to be noted that 4 patients did not received any surgery. Hematocytopenia was not detected in all the patients with splenomegaly caused by cirrhotic portal hypertension, thus it is probably a complication of splenomegaly but not an inevitable manifestation. It was concluded that splenectomy could be an effective treatment for splenomegaly associated with hematocytopenia, but patients without hematocytopenia could choose a non-surgical alternative treatment.

Gemcitabine resistance induced by interaction between alternatively spliced segment of tenascin-C and annexin A2 in pancreatic cancer cells.

Pancreatic cancer is the fourth leading cause of cancer-related death in the western countries and it is resistant to almost all cytotoxic drugs. In the current study, we explored the gemcitabine resistance induced by the interaction between Annexin A2 (ANXA2) and alternatively spliced segment of tenascin-C (TNfnA-D). In the pancreatic cancer cell culture system in vitro, it was proved that exogenous recombinant TNfnA-D combined with the cell surface ANXA2 specifically and their interaction suppressed gemcitabine-induced cytotoxicity on pancreatic cancer cells in a dose-dependent manner. Meanwhile, the TNfnA-D/ANXA2 interaction increased the phosphorylation of phosphatidylinositol 3-kinase (PI3K), Akt, inhibitory kappaB (IkappaB) kinase alpha/beta (IKKalpha/beta), IkappaBalpha, and p65 nuclear factor-kappaB (NF-kappaB) significantly. Inhibition of Akt and PI3K with their specific inhibitors partially reversed the suppression of gemcitabine-induced cytotoxicity elicited by TNfnA-D/ANXA2 interaction. Activation of p65 NF-kappaB was dependent on the phosphorylation of PI3K/Akt. The phosphorylated IKKalpha/beta induced the phosphorylation and degradation of IkappaBalpha, the sequential phosphorylation, nuclear translocation and activation of p65 NF-kappaB. Pyrrolidine dithiocarbamate (PDTC) effectively blocked the activity of p65 NF-kappaB in response to TNfnA-D. Down-regulation of p65 NF-kappaB with its specific small interfering RNA (siRNA) restored the gemcitabine-induced cytotoxicity suppressed by TNfnA-D/ANXA2 interaction. For the first time, this study show that ANXA2/TNfnA-D interaction induced gemcitabine resistance via the canonical PI3K/Akt/NF-kappaB signaling pathways in pancreatic cancer cells. Therefore, therapy targeting ANXA2/TNfnA-D and/or p65 NF-kappaB may have potential clinical application for patients with pancreatic cancers.

Gastrin-releasing peptide promotes the growth of HepG2 cells via EGFR-independent ERK1/2 activation.

Gastrin-releasing peptide (GRP) plays an important role in regulating tumor growth and migration. However, little is known about its role in human hepatocellular carcinoma (HCC) cells. This study explored the effect of GRP on the growth of HCC HepG2 cells and the underlying mechanisms. Expression of GRP and its cognate receptor (GRPR) were detected by immunocytochemisty, reverse transcription-PCR and Western blotting and compared between two human HCC cell lines (HepG2 and MHCC97H) and a normal hepatic cell line (HL-7702). The effects of GRP on cell proliferation and signaling pathways were examined by Western blotting, MTT assay and flow cytometry. Both GRP and GRPR were overexpressed in HepG2 and MHCC97H cells. GRP activated MAPK/ERK1/2 in HepG2 cells, leading to enhanced proliferation, reduced apoptosis and accelerated cell cycle progression. The effect of GRP on ERK1/2 was effectively attenuated by the GRPR antagonist PD176252 or MEK inhibitor U0126, but not by the TNF-alpha protease inhibitor TAPI-1 or the EGFR tyrosine kinase inhibitor PD153035. The effect of GRP on the growth of HepG2 cells was significantly attenuated by PD176252 or U0126. GRP serves as a mitogen for HepG2 and MHCC97H cells. GRP promotes the growth of HepG2 cells through interaction with GRPR co-expressed in tumor cells, and subsequently activates MAPK/ERK1/2 via EGFR-independent mechanisms.

Gastrin-releasing peptide links stressor to cancer progression.

INTRODUCTION: Gastrin-releasing peptide (GRP) plays an important role in cancer growth and metastasis; however, the mechanisms of how GRP affects cancer progression are not well understood. Recent studies revealed that chronic stress is a major risk factor for cancer progression, and this effect may be mediated by GRP. In this review, we will discuss the mechanisms and implications of GRP linking stressor to cancer progression. MATERIALS AND METHODS: We retrieved the studies of the relationship between GRP, stress and cancers through PubMed using systematic methods to search, select, and evaluate the findings. RESULTS: The results suggested that GRP can mediate the effects of stress on cancers at systemic, tissue and cellular levels: Stress elicits the secretion of GRP in the brain and GRP in turn activates the stress response pathways resulting in an elevation of stress hormones and GRP in the plasma and tissues. GRP in synergy with stress hormones stimulates the growth and invasion of cancer cells by suppressing the anti-tumor immune function and directly activating the pro-proliferative and pro-migratory signaling pathways in cancer cells. CONCLUSION: GRP is a multi-functional peptide, which acts as a stress mediator as well as a growth factor linking stressor to cancer progression. GRP and its high-affinity receptor are useful targets for the diagnosis and treatment of cancers.