Larotrectinib induces autophagic cell death through AMPK/mTOR signalling in colon cancer.

Larotrectinib (Lar) is a highly selective and potent small-molecule inhibitor used in patients with tropomyosin receptor kinase (TRK) fusion-positive cancers, including colon cancer. However, the underlying molecular mechanisms specifically in patients with colon cancer have not yet been explored. Our data showed that Lar significantly suppressed proliferation and migration of colon cancer cells. In addition, Lar suppressed the epithelial-mesenchymal transition (EMT) process, as evidenced by elevation in E-cadherin (E-cad), and downregulation of vimentin and matrix metalloproteinase (MMP) 2/9 expression. Furthermore, Lar was found to activate autophagic flux, in which Lar increased the ratio between LC3II/LC3I and decreased the expression of p62 in colon cancer cells. More importantly, Lar also increased AMPK phosphorylation and suppressed mTOR phosphorylation in colon cancer cells. However, when we silenced AMPK in colon cancer cells, Lar-induced accumulation of autolysomes as well as Lar-induced suppression of the EMT process were significantly diminished. An in vivo assay also confirmed that tumour volume and weight decreased in Lar-treated mice than in control mice. Taken together, this study suggests that Lar significantly suppresses colon cancer proliferation and migration by activating AMPK/mTOR-mediated autophagic cell death.

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.

A homodimeric IL-15 superagonist F4RLI with easy preparation, improved half-life, and potent antitumor activities.

Interleukin-15 (IL-15) is a promising candidate for cancer immunotherapy due to its potent immune-activating effects. There are several IL-15 molecules currently in clinical trials but facing shortages of poor half-life, circulation instability, or complicated production and quality control processes. The aim of this study is to design a novel IL-15 superagonist to set out the above difficulties, and we constructed F4RLI consisting of the GS-linker spaced IgG4 Fc fragment, soluble IL-15 Rα (sIL-15Rα), and IL-15(N72D). Using a single plasmid transient transfection in HEK293E cells, the matured F4RLI was secreted in the form of homodimer and got purified by an easy step of protein A affinity chromatography. The F4RLI product can significantly stimulate the proliferation of human CD3+CD8+ T cells and NK cells in vitro. Meanwhile, F4RLI greatly extended the half-life and prolonged the exposure of IL-15 in mice nearly by 28- and 200-fold, respectively, in comparison with that of the IL-15 monomer. In vivo, F4RLI vastly expanded mouse splenic CD8+ T lymphocytes, illustrating its potential in tumor immunotherapy. Further studies showed that the combination of F4RLI with the immune checkpoint blocker atezolizumab played a synergistic effect in treating MC38 mouse tumor by increasing the percentage of CD8+ T cells in tumor tissue. Moreover, the combination therapy of F4RLI with the angiogenesis inhibitor bevacizumab resulted in significant tumor growth suppression in a xenograft human HT-29 mouse model. Overall, our results demonstrate a homodimeric IL-15 superagonist F4RLI with advances in manufacturing processes and biopharmaceutical applications for cancer immunotherapy. KEY POINTS: • The homodimeric structure of F4RLI facilitates its easy production processes and quality control. • The fusion with Fc and sIL-15Rα extends the plasma half-life of IL-15 by about 28-fold. • F4RLI can play synergistic antitumor activity with the PD-1/PD-L1 checkpoint inhibitor or angiogenesis inhibitor.

LncRNA MCF2L-AS1 aggravates the malignant development of colorectal cancer via targeting miR-105-5p/RAB22A axis.

BACKGROUND: Colorectal cancer (CRC) represents one of the major malignant cancers in the world. It has been demonstrated that long non-coding RNAs (lncRNAs) can cause great influences on various human cancers. Though MCF.2 cell line derived transforming sequence like antisense RNA 1 (MCF2L-AS1) and its carcinogenic effect in CRC has been elucidated by several previous researches, the underlying mechanism remains unknown. AIM: We aimed at exploring the function and regulatory mechanism of MCF2L-AS1 in CRC. METHODS: MCF2L-AS1 expression in CRC cells was tested via RT-qPCR assay. The effects of MCF2L-AS1 on the biological properties of CRC cells were testified through functional experiments. The molecular mechanism of MCF2L-AS1 was verified through mechanism experiments. RESULTS: MCF2L-AS1 was highly expressed in CRC cells, and it could enhance the proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) process of CRC cells. MiR-105-5p was sponged by MCF2L-AS1 in CRC cells and Ras-related protein Rab-22A (RAB22A) was verified to be the downstream target of miR-105-5p. It was verified through rescue assays that RAB22A overexpression or miR-105-5p silencing could reverse the repressive impact of MCF2L-AS1 silencing on CRC progression. CONCLUSION: MCF2L-AS1 accelerated the malignant development of CRC cells by targeting the miR-105-5p/RAB22A axis.

EIF3B promotes cancer progression in pancreatic cancer.

BACKGROUND: This study aimed to analyze the relative expression of Eukaryotic Translation Initiation Factor 3 Subunit B (EIF3B) in pancreatic cancer and elucidate its contribution to this disease. METHODS: Relative expression of EIF3B in pancreatic cancer was analyzed by immunohistochemistry. Cell viability was determined by the MTT assay and cell proliferation was measured by direct cell counting. Cell apoptosis was detected by Annexin V staining followed by flow cytometry analysis, and cell cycle was analyzed by PI staining. The differential expression gene analysis was performed by microarray. Tumor progression in response to EIF3B deficiency in vivo was investigated using the xenograft tumor model. RESULTS: We found aberrantly high expression of EIF3B in pancreatic cancer, which associated with unfavorable prognosis. Knockdown of EIF3B greatly compromised cell viability and proliferation in both SW1990 and PANC-1 cells. Furthermore, EIF3B deficiency induced cell cycle arrest and spontaneous apoptosis. In vivo tumor progression was significantly suppressed by EIF3B silencing in the xenograft mouse model. Mechanistically, we characterized down-regulation of CDH1 and IRS1 and up-regulation of DDIT3, PTEN and CDKN1B, in response to EIF3B knockdown, which might mediate the oncogenic effect of EIF3B in pancreatic cancer. CONCLUSIONS: Our data uncovered the oncogenic role of EIF3B in pancreatic cancer.

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.

LncRNA CYTOR promotes pancreatic cancer cell proliferation and migration by sponging miR-205-5p.

BACKGROUND/AIMS: Studies have found that LncRNA CYTOR is an important regulator of cancer. However, the function of lncRNA CYTOR in pancreatic cancer (PC) is unclear. This study amid to explore the regulation of lncRNA CYTOR in PC. METHODS: The expression of CYTOR and miR-205-5p in PC was detected by RT-qPCR. CCK-8 assay, colony formation assay and scratch test were conducted to detect the effects of CYTOR and miR-205-5p on proliferation and migration of PC cells. Target gene prediction and screening and luciferase reporter assays were used to verify downstream target genes of CYTOR and miR-205-5p. The expression of Cyclin-dependent protein kinase 6 (CDK6) was detected by Western blotting. The tumor growth in mice was detected by in vivo experiments in nude mice. RESULTS: The expression of LncRNA CYTOR was significantly elevated in PC. Knockdown of CYTOR significantly inhibited cell proliferation and migration of PC cells. In vivo animal studies showed that CYTOR promoted tumor growth. MiR-205-5p was a direct target of CYTOR, and the expression levels of miR-205-5p were significantly reduced in PC cell lines. Furthermore, co-transfection of shCYTOR with miR-205-5p inhibitor partially abolished the effect of shCYTOR on cell proliferation and migration. In addition, CYTOR was negatively correlated with the expression of miR-205-5p. CDK6 was a direct target of miR-205-5p, and miR-205-5p mimic and sh CYTOR significantly reduced the expression levels of CDK6. CONCLUSION: CYTOR can promote PC progression by modulating the miR-205-5p/CDK6 axis, which may be a potential therapeutic target for PC.

Circulating circRNA Has_Circ_0141633 Serves as a Potential Biomarker for Gastric Cancer.

BACKGROUND: The current study aims to investigate the expression of circRNA has_circ_0141633 in the tissues and serum of patients with gastric cancer (GC). METHODS: RT-qPCR was used to detect the expression of has_circ_0141633 in the tissues and serum of patients with GC. Pearson's correlation was used to analyze the relationship between the level of serum and tissue has_circ_0141633 in GC patients. Receiver characteristic curve (ROC) was used to evaluate the diagnostic value of the expression of serum has_circ_0141633 in GC patients. The relationship between serum has_circ_0141633 and the clinicopathological characteristic was analyzed in GC patients. Kaplan-Meier method was used to analyze the survival rate. RESULTS: The level of serum and tissue has_circ_0141633 in GC patients was significantly higher than that in controls. Pearson's correlation analysis showed a positive correlation between serum and tissue has_circ_0141633 levels (r = 0.846, p < 0.05). ROC curve analysis showed that the AUC of serum has_circ_0141633 was 0.835 (95% CI: 0.753 - 0.916), with the sensitivity and specificity of 84.5% and 93.6%. The level of serum has_circ_0141633 was significantly increased according to the malignant characteristics of tumor diameter, differentiation, lymph node metastasis, and TNM stage. The median survival time of GC patients with low expression of has_circ_0141633 was longer than that of GC patients with high expression of has_circ_0141633. CONCLUSIONS: In summary, upregulation of serum has_circ_0141633 may be expected to be a specific molecular marker for the diagnosis and evaluation of malignant GC.

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.

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.

A potential anatomic subtype of short bowel syndrome: a matched case-control study.

BACKGROUND: Fundamental researches suggest that ileum presents greater adaptive potential than the jejunum. However, few studies estimate the association between ileum and adaptive potential in human. To discover the association, we conducted this matched case-control study. METHODS: A 1:2 pair-matched, case-control study was conducted from January 1, 2001 to January 1, 2015 in Intestinal Rehabilition and Transplant Center. The case group was ileum predominated (IP) group and the control group was jejunum predominated (JP) group. Demographic data, medical history and progression of each patient were collected. RESULTS: There were 24 IP cases and 48 JP controls in this study. The cumulative probabilities of parenteral nutrition (PN) weaning in IP group were higher than that in JP group. The Bristol stool scale scores of IP group were lower than that of JP group at third month. The Cox proportional hazards regression model confirmed that IP had a higher odds of PN weaning (OR = 2.69; 95 % CI: 1.27, 5.70, p = 0.01) as compared with JP group. The conditional logistic regression with 1:2 matching also confirmed IP group had a higher odds (OR = 4.84; 95 % CI: 2.02, 11.56, p <0.01). CONCLUSIONS: Our results indicated that ileum presents greater adaptive potential than the jejunum in nutrition and fluid absorption. And a potential anatomic subtype of short bowel syndrome was proposed. Further research need to be conducted to more fully understand the adaptive potential of ileum besides nutrition and fluid absorption.

Biomarkers for assessing mucosal barrier dysfunction induced by chemotherapy: Identifying a rapid and simple biomarker.

BACKGROUND: Chemotherapy-induced mucosal barrier dysfunction is of clinical interest. However, the assessment of mucosal barrier dysfunction still poses challenges. In this study, we compared several biomarkers with the dual sugar gut permeability test for assessing mucosal barrier dysfunction during chemotherapy. METHODS: Forty-two patients with gastric or colorectal cancer underwent chemotherapy, including FAM or FOLFOX4 regimens. Patients were asked to grade and record their symptoms of gastrointestinal toxicity daily. The urinary lactulose-mannitol ratio was measured to assess the intestinal permeability. Plasma levels of citrulline, diamine oxidase (DAO), D-lactic acid, and endotoxin were also measured. Intestinal permeability was observed in the subgroup of patients with diarrhea or constipation. RESULTS: The urinary lactulose-mannitol ratio and plasma citrulline levels increased on the third and sixth post-chemotherapy days, respectively. There were no significant differences in the plasma levels of D-lactic acid, endotoxin or DAO activity compared to their levels before chemotherapy. The urinary lactulose-mannitol ratio in diarrhea patients was significantly higher than in constipation patients. CONCLUSIONS: These results indicate that the urinary lactulose-mannitol ratio and plasma citrulline level are appropriate biomarkers for assessing mucosal barrier dysfunction in patients receiving chemotherapy. Mucosal barrier dysfunction in diarrhea patients was greater than in constipation patients.

Tremella fuciformis polysaccharides induce ferroptosis in Epstein-Barr virus-associated gastric cancer by inactivating NRF2/HO-1 signaling.

Approximately 10% of gastric cancers are associated with Epstein-Barr virus (EBV). Tremella fuciformis polysaccharides (TFPs) are characterized by antioxidative and anti-inflammatory effects in different diseases. However, whether TFP improves EBV-associated gastric cancer (EBVaGC) has never been explored. The effects of TFP on EBV-infected GC cell viability were determined using a CCK-8 assay and flow cytometry. Western blotting and RT-qPCR were performed to explore the expression of ferroptosis-related proteins. The CCK-8 assay showed that TFP decreased EBV-infected GC cell viability in a dose- and time-dependent manner. Flow cytometry assays indicated that TFP significantly induced EBV-infected GC cell death. TFP also reduced the migratory capacity of EBV-infected GC cells. Furthermore, treatment with TFP significantly increased the mRNA levels of PTGS2 and Chac1 in EBV-infected GC cells. Western blot assays indicated that TFP suppressed the expression of NRF2, HO-1, GPX4 and xCT in EBV-infected GC cells. More importantly, overexpression of NRF2 could obviously rescue TFP-induced downregulation of GPX4 and xCT in EBV-infected GC cells. In summary, we showed novel data that TFP induced ferroptosis in EBV-infected GC cells by inhibiting NRF2/HO-1 signaling. The current findings may shed light on the potential clinical application of TFP in the treatment of EBVaGC.

Reinforcement methods of duodenal stump after laparoscopic gastrectomy for gastric cancer: A review.

Duodenal stump fistula is a rare but dangerous complication of gastric cancer surgery. Reinforcement of the duodenal stump was suggested as a useful method to prevent the occurrence of duodenal stump fistula. Although laparoscopic surgery has been established as a safe procedure for gastric cancer, it is acknowledged that the application of duodenal stump reinforcement is a demanding process in laparoscopic radical gastrectomy. This review aims to provide a concise description of the proposed reinforcement methods of duodenal stump after laparoscopic radical gastrectomy for gastric cancer by summarizing the relevant literature written in English. The thorough knowledge of these reinforcement techniques may help surgeons to find the most suitable reinforcement method of duodenal stump for patients.

Synergistic antitumor activity of regorafenib and rosuvastatin in colorectal cancer.

Introduction: Colorectal cancer is one of the most prevalent life-threatening malignant tumors with high incidence and mortality. However, the efficacy of current therapeutic regimens is very limited. Regorafenib has been approved for second- or third-line treatment of patients who are refractory to standard chemotherapy diagnosed with metastatic colorectal cancer, but its clinical efficacy needs to be further improved. Accumulating evidence demonstrates that statins also possess potent anticancer activities. However, whether regorafenib and statins pose synergistic anticancer effects in colorectal cancer is still unclear. Methods: Sulforhodamine B (SRB) assays were applied to evaluate the anti-proliferative activity of regorafenib or/and rosuvastatin in vitro, and immunoblotting analysis were applied to detect the effects of regorafenib/rosuvastatin combined treatment on mitogen-activated protein kinase (MAPK) signaling and apoptosis-related proteins. MC38 tumors were applied to investigate the synergistic anticancer effects of regorafenib in combination with rosuvastatin in vivo. Results: We found that regorafenib in combination with rosuvastatin exerted significant synergistic inhibition against colorectal cancer growth in vitro and in vivo. Mechanistically, regorafenib and rosuvastatin combination synergistically suppressed MAPK signaling, a crucial signaling pathway promoting cell survival, as indicated by the reduction of phosphorylated MEK/ERK. In addition, regorafenib in combination with rosuvastatin synergistically induced the apoptosis of colorectal cancer in vitro and in vivo. Discussion: Our study demonstrated the synergistic anti-proliferative and pro-apoptotic effects of regorafenib/rosuvastatin combined treatment in colorectal cancer in vitro/vivo and might potentially be evaluated as a novel combination regimen for clinical treatment of colorectal cancer.

[Retracted] Exosomal miR­130a­3p promotes the progression of differentiated thyroid cancer by targeting insulin­like growth factor 1.

[This retracts the article DOI: 10.3892/ol.2021.12544.].

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.

Association of RASSF1A Ala133Ser polymorphism with cancer risk: a updated meta-analysis involving 7362 subjects.

It has been demonstrated in many studies that the polymorphism of Ras association domain family 1 isoform A (RASSF1A) is related to tumor risk; however, this conclusion remains a controversy. In this study, we systemically retrieved relevant studies in electronic databases such as PUBMED, and EMBASE, and calculated odds ratios (ORs) as well as relevant 95% confidence intervals (CIs). Besides, meta-package in STATA version 12.0 was used. This meta-analysis finally included altogether 12 studies with 16 case-control articles. According to our data, the polymorphism of RASSF1A Ala133Ser was associated with tumor risk (Ser vs. Ala: OR = 1.68,95% CI = 1.20-2.36; Ala/Ser vs. Ala/Ala:OR = 1.63,95% CI = 1.16-2.27; Ser/Ser vs. Ala/Ala:OR = 3.06,95% CI = 1.91-4.89; Recessive model:OR = 2.67, 95% CI = 1.66-4.32; Dominant model: OR =1.72, 95% CI =1.20-2.45). Further, subgroup analyses stratified based on race and cancer type indicated this polymorphism is related to lung cancer(LC) and hepatocellular carcinoma(HCC) susceptibility in Asians.In conclusion, we found that RASSF1A Ala133Ser polymorphism increased LC and HCC risk in Asians, which requires large-scale, delicately-designed researches for verification.

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.