Knockdown of EIF3H inhibits the development and progression of pancreatic cancer by regulating cell proliferation and apoptosis in vitro.

Nowadays, pancreatic cancer has been recognized as one of the most fatal malignancies worldwide, the molecular mechanism of which is still not fully understood. In this study, we aimed to uncover the fundamental functions of the eukaryotic translation initiation factor 3H subunit (EIF3H) in the development and progression of pancreatic cancer. Firstly, the results of immunohistochemical (IHC) staining revealed that EIF3H was highly expressed in pancreatic cancer. Moreover, lentiviruses were used to deliver shRNAs into pancreatic cancer cells for silencing EIF3H. Furthermore, the loss-of-function assays demonstrated that knockdown of EIF3H could inhibit the progression of pancreatic cancer cells by reducing proliferation capacity, promoting apoptosis, arresting cell cycle in G2 and suppressing cell migration. In summary, EIF3H may play a critical role in the development and progression of pancreatic cancer, which possesses the potential to act as a therapeutic target for pancreatic cancer treatment.

Long noncoding RNA (lncRNA) HOTAIR: Pathogenic roles and therapeutic opportunities in gastric cancer.

Gastric cancer is one of the first malignant cancers in the world and a large number of people die every year due to this disease. Many genetic and epigenetic risk factors have been identified that play a major role in gastric cancer. HOTAIR is an effective epigenetic agent known as long noncoding RNA (lncRNA). HOTAIR has been described to have biological functions in biochemical and cellular processes through interactions with many factors, leading to genomic stability, proliferation, survival, invasion, migration, metastasis, and drug resistance. In the present article, we reviewed the prognostic value of the molecular mechanisms underlying the HOTAIR regulation and its function in the development of Gastric Cancer, whereas elucidation of HOTAIR-protein and HOTAIR-DNA interactions can be helpful in the identification of cancer processes, leading to the development of potential therapeutic strategies.

Investigating the Mechanisms of Jieduquyuziyin Prescription Improves Lupus Nephritis and Fibrosis via FXR in MRL/lpr Mice.

Lupus nephritis (LN) is one of the most serious complications of systemic lupus erythematosus (SLE) and one of the leading causes of death. An alternative effective treatment to ameliorate and relieve LN and delay the process of renal tissue fibrosis is urgently needed in the clinical setting. Jieduquyuziyin prescription (JP) has been successfully used to treat SLE, but its potential mechanisms are not sufficiently understood. In this study, we treated MRL/lpr mice with JP for 8 weeks and treated human renal tubular epithelial cells (human kidney 2 (HK-2)) with drug-containing serum to observe the antagonistic effects of JP on inflammation and fibrosis, as well as to investigate the possible mechanisms. Results demonstrated that JP significantly reduced urinary protein and significantly improved pathological abnormalities. Metabolomics combined with ingenuity pathway analysis illustrated that the process of kidney injury in lupus mice may be closely related to farnesoid X receptor (FXR) pathway abnormalities. Microarray biomimetic analysis and LN patients indicated that FXR may play a protective role as an effective therapeutic target for LN and renal fibrosis. JP significantly increased the expression of FXR and inhibited the expression of its downstream targets, namely, nuclear transcription factor κB (NF-κB) and α-smooth muscle actin (α-SMA), in the kidney of MRL/lpr mice and HK-2 cells, as confirmed by in vitro and in vivo experiments. In conclusion, JP may mediate the activation of renal FXR expression and inhibit NF-κB and α-SMA expression to exert anti-inflammatory and antifibrotic effects for LN prevention and treatment.

LncRNA PVT1 Regulates miR-1207-5p to Affect Colon Cancer Proliferation and Migration via the Wnt6/ß-catenin2 Pathway.

Background: We aimed to evaluate the effects of lncRNA PTV1 on colon cancer proliferation and migration via the Wnt6/ß-catenin2 pathway. Materials and Methods: A total of 117 colon cancer and normal adjacent tissue samples were collected. LncRNA PVT1 and miR-1207-5p expressions in these samples and colon cancer cell lines were detected by Quantitative reverse transcription-polymerase chain reaction (qRT-PCR). LncRNA PVT1-silencing cells and miR-1207-5p-overexpressing Caco-2-siPVT1 cells were constructed, respectively. The effects of lncRNA PVT1 silencing on cell proliferation were assessed by MTT and colony formation assays. The effects on invasion and migration were tested by Transwell and scratch assays respectively. The targeting regulatory relationship between miR-1207-5p and Wnt6 was analyzed by a dual-luciferase reporter assay. The relationship between lncRNA PVT1 and miR-1207-5p was studied by RNA-binding protein immunoprecipitation and RNA pull-down assays. The expressions of proteins in the Wnt6/ß-catenin2 pathway were detected by Western blotting. Results: The lncRNA PVT1 mRNA expression in colon cancer tissue was significantly higher than that in normal adjacent tissue (p < 0.05). The expression in lncRNA PVT1-silencing cells was significantly down-regulated (p < 0.05). The colonies of Caco-2-siPVT1 cells decreased, accompanied by a reduced number of cells penetrating Matrigel and migration (p < 0.05). Compared with siPVT1 + NC group, the number of colonies and migration of siPVT1 + miR-1207-5p-overexpressing group increased significantly (p < 0.05). There was a targeting relationship between miR-1207-5p and PVT1. MiR-1207-5p had a targeted binding site with Wnt6. The protein expressions of Wnt6/ß-catenin2 in Caco-2-siPVT1 group were significantly lower than those of control and Caco-2-siNC groups (p < 0.05). Conclusion: LncRNA PVT1 was highly expressed in colon cancer. It may enhance the proliferation and migration of colon cancer cells by up-regulating miR-1207-5p level and enhancing the Wnt6/ß-catenin2 pathway.

Ginsenoside Rg3 ameliorates acute pancreatitis by activating the NRF2/HO­1­mediated ferroptosis pathway.

Acute pancreatitis (AP) is an inflammatory disorder that has been associated with systemic inflammatory response syndrome. Ginsenoside Rg3 is a major active component of Panax ginseng, which has been demonstrated to exert potent protective effects on hyperglycemia and diabetes. However, it remains to be determined whether Rg3 ameliorates AP. Thus, an in vitro AP cell model was established in the present study by exposing AR42J cells to cerulein (Cn). AR42J cell viability was increased in the Rg3­treated group as compared with the Cn­exposed group. Simultaneously, the number of dead AR42J cells was decreased in the Rg3­treated group compared with the group treated with Cn only. Furthermore, following treatment with Rg3, the production of malondialdehyde (MDA) and ferrous ion (Fe2+) in the AR42J cells was reduced, accompanied by increased glutathione (GSH) levels. Western blot analysis revealed that the decrease in glutathione peroxidase 4 (GPX4) and cystine/glutamate transporter (xCT) levels induced by Cn were reversed by Rg3 treatment in the AR42J cells. Mice treated with Cn exhibited increased serum amylase levels, as well as increased levels of TNFα, IL­6, IL­1ß, pancreatic MDA, reactive oxygen species (ROS) and Fe2+ production. Following Rg3 treatment, ROS accumulation and cell death were decreased in the pancreatic tissues compared with the AP group. Furthermore, in the pancreatic tissues of the AP model, the expression of nuclear factor­erythroid factor 2­related factor 2 (NRF2)/heme oxygenase 1 (HO­1)/xCT/GPX4 was suppressed. In comparison, the NRF2/HO­1/xCT/GPX4 pathway was activated in pancreatic tissues following Rg3 administration. Taken together, the present study, to the best of our knowledge, is the first to reveal a protective role for Rg3 in mice with AP by suppressing oxidative stress­related ferroptosis and the activation of the NRF2/HO­1 pathway.

[Corrigendum] miR­23a suppresses pancreatic cancer cell progression by inhibiting PLK­1 expression.

Subsequently to the publication of this paper, the authors have realized that they made an error during the sorting of the data panels shown for the migration and invasion assays shown in Fig. 2C; essentially, the 'Invasion/PLL3.7' panel was chosen from the same original data source as the panel selected to represent the 'Migration/Inhibitor­NC' experiment. The authors have consulted their original data, and realize that the 'Invasion/PLL3.7' data panel was inadvertently selected incorrectly for Fig. 2. The revised version of Fig. 2, showing the data appropriate for the 'Invasion/PLL3.7' experiment, is shown on the next page. Note that the errors made in assembling Fig. 2 did not significantly affect either the results or the conclusions reported in this paper, and all the authors agree to this Corrigendum. The authors are grateful to the Editor of Molecular Medicine Reports for allowing them the opportunity to publish this corrigendum, and apologize to the readership for any inconvenience caused.[Molecular Medicine Reports 18: 105­112, 2018; DOI: 10.3892/mmr.2018.8941].

Efficiency of complete omentectomy in patients with resectable gastric cancer: a meta­analysis and systematic review.

BACKGROUND: We performed a meta-analysis to investigate the efficacy of complete omentectomy (CO) in patients undergoing radical gastrectomy for gastric cancer. METHODS: We conducted a literature search in PubMed, Web of Science, and the Cochrane Library databases for clinical research that compared CO with non-complete omentectomy (NCO). These articles were published prior to April 2021. Overall survival (OS) rates, relapse-free survival (RFS) rates, recurrence rates, operation times, estimates of blood loss, numbers of harvested lymph nodes, complications, and lengths of hospital stays were compared using relative risks (RRs) and weighted mean differences (WMDs). RevMan 5.3 software was used for statistical analysis. RESULTS: Nine studies that included 3329 patients (1960 in the CO group) and 1369 in the NCO group comprised the analysis. The meta-analysis showed that CO was associated with a decreased 3-year OS rate (RR = 0.94, 95% CI 0.90-0.98, P = 0.005) and 5-year OS rate (RR = 0.93, 95% CI 0.88-0.98, P = 0.007). However, it was not associated with the 3-year RFS rate (RR = 0.97, 95% CI 0.90-1.04, P = 0.44), 5-year RFS (RR = 0.98, 95% CI 0.90-1.06, P = 0.60), or recurrence rate (RR = 1.17, 95% CI 0.95-1.45, P = 0.15) compared to the NCO group. For surgical-related outcomes, significant heterogeneity existed between the studies. Compared to the NCO group, CO was found to be associated with significantly more estimated blood loss (WMD = 250.90, 95% CI 105.90-396.28, P = 0.0007) and less harvested lymph nodes (WMD = - 3.59, 95% CI - 6.88, - 0.29, P = 0.03). Although, there was no significant difference in the surgical time (WMD = 15.93, 95% CI - 0.21, 32.07, P = 0.05). No statistically significant differences were observed in the rates of overall (P = 0.79) and major complications (P = 0.90), or the lengths of hospital stays (P = 0.11) between the two groups. CONCLUSIONS: Based on the available evidence, CO is not superior to NCO in terms of survival. CO is not recommended as a routine surgery for gastric cancer. Future well-designed high-quality RCTs are warranted.

Exosomal NNMT from peritoneum lavage fluid promotes peritoneal metastasis in gastric cancer.

Peritoneal metastasis (PM) is the major cause of recurrence in patients with gastric cancer (GC) and is associated with poor prognosis. The oncogenic role of Nicotinamide N-methyltransferase (NNMT) in GC has been reported, but the role of secreted NNMT that is transported by exosomes remains unknown. In this study, exosomes were isolated from GC patients with or without PM and from GC cell line, including GC-114, GC-026, MKN45, and SNU-16 cells. The contents of NNMT were significantly enhanced in exosomes isolated from GC patients with PM compared with those from GC patients without PM. Furthermore, the levels of NNMT were significantly enhanced in exosomes from GC cell lines relative to those from normal human gastric epithelial cell line GES-1 cells. These data indicate that NNMT may be involved in intercellular communication for peritoneal dissemination. Moreover, colocalization of GC-derived exosomal NNMT was found in human peritoneal mesothelial cell line HMrSV5 cells. Additionally, relative to GES-1 exosomes, SNU-16 exosomes significantly activated TGF-ß/smad2 signaling in HMrSV5 cells. However, when NNMT was silenced, the activation of TGF-ß/smad2 by SNU-16 exosomes was abolished in HMrSV5 cells. We propose that NNMT-containing exosomes derived from GC cells could promote peritoneal metastasis via TGF-ß/smad2 signaling.

LncRNA MEG8 plays an oncogenic role in hepatocellular carcinoma progression through miR-367-3p/14-3-3ζ/TGFßR1 axis.

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and it carries a poor prognosis. Clarifying the pathologic mechanisms of this disease will be beneficial for the diagnosis and treatment of HCC. LncRNA MEG8 is involved in several tumors but its role in HCC progression remains unknown. This study was designed to explore the role and regulatory mechanisms of MEG8 in HCC progression. MTT, EdU, wound-healing, and transwell assays were employed to analyze the proliferation, migration, and invasion of HCC cells. A luciferase assay was utilized to confirm the predicted binding site. RNA immunoprecipitation and co-immunoprecipitation were employed to verify the binding between MEG8 and miR-367-3p as well as 14-3-3ζ and TGFßR1. Real-time PCR and western blot were employed to detect the expression of interesting genes. Results revealed that MEG8 was increased in HCC tissues and cells, and was correlated with the poor prognosis of HCC patients. Inhibiting MEG8 significantly repressed the HCC cells' ability to proliferate, migrate, and invade. Moreover, MEG8 sponged miR-367-3p to upregulate 14-3-3ζ, the binding of which suppressed TGFßR1 degradation, thereby enhancing TGFß signaling. In conclusion, this work exposed a novel role and regulatory mechanism of MEG8 in HCC and provided new insight into the treatment of HCC.

Extracellular vesicle derived miR-544 downregulates expression of tumor suppressor promyelocytic leukemia zinc finger resulting in increased peritoneal metastasis in gastric cancer.

Peritoneal metastasis (PM) is the main cause of poor prognosis in patients with advanced gastric cancer (GC). Increasing evidence has suggested that cancer-associated EVs in body fluids may assist in the diagnosis and treatment of GC. Here, we investigated the role of GC-derived EVs in PM development. Our results demonstrate that expression of the tumor suppressor promyelocytic leukemia zinc finger (PLZF) is decreased in GC tissues and PM lesions from GC patients. PLZF suppression promoted migration and invasion of peritoneal mesothelial HMrSV5 cells, while PLZF overexpression suppressed HMrSV5 cell migration and invasion. Microarray analysis revealed significantly upregulated expression of several miRNAs in EVs isolated from GC patients with PM, including miR-544. The increased miR-544 expression was confirmed in GC tissues and PM-derived EVs. Transfection with miR-544 reduced PLZF expression in HMrSV5 cells, while miR-544 inhibition increased PLZF expression. Incubation of GC cells with peritoneal mesothelial HMrSV5 cells showed that miR-544 could be transferred from GC-derived EVs to peritoneal cells, where it suppressed the PLZF expression. These findings indicate that EV-mediated transfer of miR-544 decreases the PLZF expression in PM lesions, which suggests miR-544 could potentially serve as a diagnostic biomarker and therapeutic target for treatment of GC patients.

Increased levels of miR-372 correlate with disease progression in patients with hyperlipidemic acute pancreatitis.

The aim of the present study was to investigate the expression of microRNA (miRNA)-372 in the serum of patients with hyperlipidemic acute pancreatitis (HTGAP), and its clinical significance. Patients with a serum lipid concentration ≥11.3 or 5.65-11.3 mmol/l with chylous serum were included in group A (n=40). The remaining patients did not have HTGAP and were included in group B (B). A further 25 patients with hyperlipidemia, but not AP (group C), and 30 healthy volunteers (group D) were recruited as controls. The level of miR-372 in the serum of group A (4.76±2.60) was significantly increased compared with groups B (0.98±0.80), C (0.85±0.62) and D (0.76±0.44); however, there was no significant difference in the expression of miR-372 between groups B, C and D. The expression level of miR-372 was significantly increased in the severe HTGAP group (6.45±2.20) compared with the mild HTGAP group (3.08±1.74). Further experiments suggested that the expression level of miR-372 was positively correlated with the level of triacylglycerol (r=0.666; P<0.001) but not with the level of amylase (r=-0.145; P>0.05). ROC analysis indicated that the combined use of miR-372 expression levels and Acute Physiology and Chronic Health Evaluation II scoring improved the diagnostic value for HTGAP. In summary, the expression of miR-372 in HTGAP was significantly upregulated and increased with the severity of the disease. The results of the present study may provide a novel strategy for the diagnosis and severity assessment of HTGAP in the clinic.

Diagnostic Value of miR-142-5p and Tiam-1 in Colon Cancer Patients.

BACKGROUND: The current study aims to detect the expression of miR-142-5p and T-cell lymphoma invasion and metastasis 1 (Tiam1) in colon cancer tissues and adjacent normal tissues, thereby exploring their association with clinical stage and lymph node metastasis of colon cancer. METHODS: Thirty specimens of colon cancer tissues and adjacent tissues were collected. The expressions of miR-142-5p and Tiam1 were detected by RT-PCR. The correlation between them and clinical pathology was analyzed using person correlation assay. RESULTS: The expression of miR-142-5p in colon cancer tissues (0.46 ± 0.25) was lower than that in adjacent tissues (1.00 ± 0.23), and the difference was statistically significant. The expression of Tiam1 gene in colon cancer tissues (5.46 ± 2.34) was higher than that in adjacent tissues (1.00 ± 0.43). There was a significant negative correlation between miR-142-5p and Tiam1 (r = -0.873, p < 0.01). The expression level of miR-142-5p (0.22 ± 0.07) in stage III and IV colon cancer tissues was significantly lower than that in stage I and II colon cancer tissues (0.71 ± 0.21, p < 0.05), while the expression level of Tiam1 mRNA (6.37 ± 1.98) in stage III and IV colon cancer tissues was significantly higher than that in stage I and II colon cancer tissues (2.86 ± 1.32, p < 0.05). Furthermore, the expression of miR-142-5p in colon cancer with lymph node metastasis was significantly lower than that in colon cancer without lymph node metastasis, while the expression of Tiam1 was contrary to that in colon cancer without lymph node metastasis. CONCLUSIONS: In summary, miR-142-5p and Tiam-1 may be potential diagnostic markers for colon cancer.

miR­23a suppresses pancreatic cancer cell progression by inhibiting PLK­1 expression.

The present study aimed to explore the effects and underlying mechanisms of microRNA (miR)­23a on pancreatic cancer (PC) cells progression. Reverse transcription­quantitative polymerase chain reaction and western blot analysis were used to detect the mRNA and protein miR­23a and PLK­1 level. Cell viability, cell cycle, migration and invasion assasy, and in vivo tumorigenicity assay were used to investigate the effects of miR­204. Further luciferase reporter assay was used to explore the mechanisms contributing to miR­204 effects. It was observed that miR­23a expression was upregulated and negatively associated with polo­like kinase­1 (PLK­1) expression in human PC tissues. PLK­1 was a direct target of miR­23a in PC cells. Functional analysis demonstrated that miR­23a overexpression suppressed cell proliferation, inhibited cell migration and invasion and promoted cell apoptosis in vitro. When PC cells were transfected with has­miR­23a PLK­1 was downregulated and its downstream molecules were deregulated, including decreased expression of B­cell lymphoma­2, cyclin B1 and vimentin, and increased expression of Bax and E­cadherin. The inhibitory effect of miR­23a on PC cell progression was observed in vivo tumor xenografts. The results of the study suggest that miR­23a inhibits PC cell progression by directly targeting PLK­1­associated signaling and promoting miR­23a expression may be a potential method for treating patients with PC.

Long noncoding RNA CCAL promotes gastric cancer cell proliferation and migration in a Myc dependent way.

AIMS: Long non-coding RNAs (lncRNAs) play key roles in cancers, yet their potential molecular mechanisms are not well understood. The objective of this study is to examine the expression, biological functions and mechanism of lncRNA CCAL in gastric cancer (GC). METHODS: MTT and Colony formation assay were used to detect cell proliferation and the colony formation ability of gastric cancer cells. Wound healing, Migration, and invasion assay were respectively used to explore the migration, and invasion in gastric cancer cell lines. Real-time polymerase chain reaction (RT-PCR) was performed to determine the expression level of CCAL. Western Blot was used to determine the expression of related proteins. RESULTS: In the present study, we found that CCAL was upregulated in gastric cancer cell lines. Patients whose tumors had high CCAL expression had a shorter overall survival than patients whose tumors had low CCAL expression. Overexpression CCAL promoted the proliferation, migration and invasion of GC by regulating the expression of myc. CONCLUSION: The present study reveals that CCAL is an oncogenic lncRNA that promotes the tumorigenesis and progression of GC.

Delta-shaped Billroth-I anastomosis in totally laparoscopic distal gastrectomy with D2 lymph node dissection for gastric cancer.

BACKGROUND: It is attractive to complete laparoscopic reconstruction of digestive tract as a part of totally laparoscopic distal gastrectomy for patients of distal gastric cancer with its obvious advantage of minimal invasiveness. Delta-shaped Billroth-I anastomosis provides a feasible option for these patients, as we herein describe. METHODS: A 61-year-old woman who was diagnosed with early gastric cancer (type III) of 1.0 cm in diameter at the gastric angle by gastroscopy underwent totally laparoscopic distal gastrectomy with D2 lymph node dissection and delta-shaped Billroth-I anastomosis. RESULTS: The operation lasted for about 120 min with blood loss of about 50 mL. The patient recovered well and was discharged from hospital on postoperative day 11. CONCLUSIONS: Delta-shaped Billroth-I anastomosis by laparoscopic linear staplers is a safe procedure of alimentary reconstruction for totally laparoscopic distal gastrectomy and preferred for patients with early gastric cancer at gastric angle.

The roles of APOBEC3B in gastric cancer.

Gastric cancer was the third cause of death in China. In this study, we found that the APOBEC3 (apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3) expression was higher in gastric cancer tissues than that in normal tissues and confirmed APOBEC3B expression was correlated with the unfavorable prognosis of the patients with gastric cancer. Furthermore, APOBEC3B expression was associated with gender, tumor size, histological grade, T stage, and TNM staging of the patients with gastric cancer. Down-regulation of APOBEC3B expression in MNK28 cells could enhance the cytotoxicity of PDCD2. No editing took place in PDCD2 positive MKN28 cells with APOBEC3B shRNA. These results indicated that loss of function of PDCD2 may be partly caused by APOBEC3B-induced extensive mutagenesis.

Programmed cell death 2 protein induces gastric cancer cell growth arrest at the early S phase of the cell cycle and apoptosis in a p53-dependent manner.

Programmed cell death 2 (PDCD2) is a highly conserved nuclear protein, and aberrant PDCD2 expression alters cell apoptosis. The present study aimed to investigate PDCD2 expression in gastric cancer. Tissue specimens from 34 gastric cancer patients were collected for analysis of PDCD2 expression using immunohistochemistry, western blotting and qRT-PCR. Gastric cancer cell lines (a p53-mutated MKN28 line and a wild-type p53 MKN45 line) were used to assess the effects of PDCD2 overexpression. p53-/- nude mice were used to investigate the effect of PDCD2 on ultraviolet B (UVB)-induced skin carcinogenesis. The data showed that PDCD2 expression was reduced in gastric cancer tissue specimens, and loss of PDCD2 expression was associated with the poor survival of patients. PDCD2 expression induced gastric cancer cell growth arrest at the early S phase of the cell cycle and apoptosis. The antitumor effects of PDCD2 expression were dependent on p53 expression in gastric cancer cells. Moreover, PDCD2 expression inhibited activity of the ATM/Chk1/2/p53 signaling pathway. In addition, PDCD2 expression suppressed UVB-induced skin carcinogenesis in p53+/+ nude mice, but not in p53-/- mice. The data from the present study demonstrated that loss of PDCD2 expression could contribute to gastric cancer development and progression and that PDCD2-induced gastric cancer cell growth arrest at the early S phase of the cell cycle and apoptosis are p53-dependent.