Predicting the Prognosis of Gastric Cancer by Albumin/Globulin Ratio and the Prognostic Nutritional Index.

Background: Albumin-to-globulin ratio (AGR) and the prognostic nutrition index (PNI) are used to assess the nutritional status and severity of disease for a cancer patient. However, the clinical significance of combining these two predictors in gastric cancer (GC) remains unclear. This study evaluated the prognostic value of pretreatment serum AGR and the PNI for GC.Methods: A total of 273 patients with GC, diagnosed between January 2010 and January 2014, were enrolled. The association of AGR, PNI with clinicopathological characters and prognosis were assessed by Cox regression and Kaplan-Meier methods.Results: Both low AGR group and low PNI group had poor overall survival (OS) and progression-free survival (PFS) (all p < 0.001), while patients with low AGR and PNI had the lowest OS rate. Multivariate analyses revealed that AGR (for OS HR = 0.657, 95%CI: 0.449-0.962, p = 0.031; for PFS HR = 0.684, 95%CI: 0.528-0.895, p = 0.035) was an independent prognostic factor for OS and PFS in patients with GC, and PNI was verified as a predictor for OS (HR = 0.782, 95%CI: 0.503 -0.997, p = 0.048).Conclusions: Low level of pretreatment AGR and PNI may be independent prognostic factors for patients with GC, and patients with both factors indicated the worst OS.

Elevated serum levels of interleukin-37 correlate with poor prognosis in gastric cancer.

BACKGROUND: interleukin-37 (IL-37) is as a natural suppressor of the innate inflammatory and immune responses. It has also been reported to be involved in carcinogenesis and metastasis. The present case-control study was designed to investigate the role of serum levels of IL-37 in patients with gastric cancer. METHODS: serum IL-37 levels were determined using the enzyme-linked immunosorbent assay in 180 patients diagnosed with gastric cancer and 100 healthy controls. The association between IL-37 levels and clinical factors was assessed. Univariate and multivariate analyses were performed to investigate the prognostic significance of these parameters in gastric cancer. RESULTS: serum IL-37 levels in gastric cancer patients (5.606 ± 0.837 pg/ml) were significantly higher than those in healthy controls (2.364 ± 0.210 pg/ml, p < 0.001). High serum IL-37 levels were related to a poorly differentiated histologic type (p = 0.046) and advanced T stage (p = 0.003). The Kaplan-Meier survival analysis indicated that the high-IL-37 group had a poorer overall survival and progression-free survival (overall survival [OS]: 39.0 months vs 13.0 months, p < 0.001, progression-free survival [PFS]: 25.0 months vs 10.0 months, p < 0.001). Multivariate analyses showed serum IL-37 to be an independent prognostic factor for gastric cancer patients (OS: hazard ratios [HR] = 1.842, 95% CI: 1.190-2.854, p = 0.006; PFS: HR = 1.547, 95% CI: 1.014-2.359, p = 0.043). CONCLUSIONS: in conclusion, serum IL-37 levels were associated with poor overall survival and progression-free survival in gastric cancer patients. IL-37 may be a potential predictor of prognosis in gastric cancer.

C6 ceramide dramatically increases vincristine sensitivity both in vivo and in vitro, involving AMP-activated protein kinase-p53 signaling.

Use of the conventional cancer chemotherapy (i.e. vincristine) is limited in tumor cells exhibiting pre-existing or acquired resistance. Here, we found that C6 ceramide (C6) dramatically sensitized vincristine's activity. In vitro, C6 and vincristine coadministration induced substantial necrosis and apoptosis in multiple human cancer cell lines, which were accompanied by a profound AMP-activated protein kinase (AMPK) activation, subsequent p53 activation, mTORC1 inactivation and Bcl-2/HIF-1α downregulation. Such synergistic effects were attenuated by AMPK inactivation through genetic mutation or short hairpin RNA silencing. Coadministration-activated p53 translocated to mitochondria, and formed a complex with cyclophilin-D, leading to mitochondrial permeability transition pore opening and cell necrosis. Disrupting p53-Cyp-D complexation through pharmacological or genetic means reduced costimulation-induced cytotoxicity. In vivo, a liposomal C6 was synthesized, which dramatically enhanced the antiproliferative activity of vincristine on HCT-116 or A2780 xenografts. Together, C6 sensitizes vincristine-induced anticancer activity in vivo and in vitro, involving activating AMPK-p53 signaling.

MicroRNA-101 down-regulates sphingosine kinase 1 in colorectal cancer cells.

MicroRNAs (miRs) dysregulation is a general feature of colorectal cancer (CRC) and other solid tumors, and is associated cancer progression. In the current study, we demonstrate that microRNA-101 (miR-101) inhibits CRC cells probably through down-regulating sphingosine kinase 1 (SphK1). Our results showed that exogenously expressing miR-101 inhibited CRC cell (HT-29 and HCT-116 lines) growth in vitro. At the molecular level, miR-101 dramatically down-regulated SphK1 mRNA and protein expression, causing pro-apoptotic ceramide production in above CRC cells. On the other hand, inhibition of miR-101 through expressing antagomiR-101 increased SphK1 expression to down-regulate ceramide level in HT-29 cells. miR-101 expression increased the in vitro anti-CRC activity of conventional chemo-agents: paclitaxel and doxorubicin. CRC cells with SphK1-shRNA knockdown showed similar phenotypes as the miR-101-expressed CRC cells, presenting with elevated level of ceramide and high sensitivity to paclitaxel or doxorubicin. In vivo, HCT-116 xenograft growth in severe combined immuno-deficient (SCID) mice was dramatically inhibited by over-expressing miR-101. Further, miR-101 enhanced paclitaxel-induced anti-HCT-116 activity in vivo. Together, these results indicate that miR-101 exerts its anti-CRC activities probably through down-regulating SphK1.

Association of Interleukin-10 -3575T>A and -1082A>G polymorphisms with non-Hodgkin lymphoma susceptibility: a comprehensive review and meta-analysis.

A number of studies have investigated the associations between IL-10 polymorphisms and non-Hodgkin lymphoma (NHL) susceptibility; however, the conclusions were still contradictory. To acquire a more precise estimation of the association, we performed the current meta-analysis. We systematically searched publications from EMBASE and MEDLINE, and calculated pooled odds ratios (ORs) and 95 % confidence intervals (CIs) using either fixed-effects or random-effects model. Genotype-based IL-10 mRNA expression analysis was performed using online public database of 270 individuals with three different ethnicities. A total of 10,703 cases and 11,823 controls from 10 studies were included for the -3575T>A polymorphism, 10,226 cases and 12,215 controls from 17 studies for the -1082A>G polymorphism. Pooled results indicated that IL-10 -3575T>A was associated with increased risk of diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL), especially for Caucasians and hospital-based population. There was no association between IL-10 -1082A>G and NHL risk. However, subgroup analysis showed that IL-10 -1082GG might confer increased susceptibility to FL. In summary, this meta-analysis indicated that -3575T>A polymorphism was associated with altered NHL susceptibility for Caucasians and hospital-based population, especially for DLBCL and FL subtypes. The -1082A>G polymorphism may contribute to increased FL risk. Further large-scale population studies among different ethnicities are needed to validate these results.

The association between NQO1 Pro187Ser polymorphism and urinary system cancer susceptibility: a meta-analysis of 22 studies.

Numerous studies have investigated the association between NQO1 Pro187Ser polymorphism and urinary system cancer risk, but the findings are inconsistent. To derive a more precise estimation of such association, we performed a meta-analysis based on 22 publications encompassing 5,274 cases and 6,459 controls. Overall, significant association was found between NQO1 Pro187Ser polymorphism and urinary system cancer risk. Moreover, stratified analysis observed a statistically significant association for bladder cancer, prostate cancer, renal cell carcinoma, Caucasians, Asians, and hospital-based studies. In summary, this meta-analysis indicated that NQO1 Pro187Ser polymorphism conferred genetic susceptibility to urinary system cancer.

Prognostic value of TROP2 expression in patients with gallbladder cancer.

Altered expression of TROP2 is observed in various types of human cancers. However, the clinical significance and pathological role of TROP2 in gallbladder cancer (GBC) remains unclear. The main objective of this investigation was to clarify the relationships between TROP2 expression and the clinicopathological features of patients with GBC. Immunohistochemistry was performed to investigate the expression of TROP2 and epithelial-mesenchymal transition (EMT) indicator proteins in 93 patients with GBC. Immunohistochemistry showed that the protein expression level of TROP2 was significantly higher in GBC tissues than in adjacent noncancerous tissues. In addition, immunohistochemistry analysis showed that TROP2 expression was significantly correlated with histologic grade (P=0.038), tumor stage (P=0.015), and lymph node metastasis (P=0.007). Furthermore, high TROP2 expression was significantly associated with a loss of the epithelial marker E-cadherin (P=0.013) and acquisition of expression of the mesenchymal marker vimentin (P=0.031). Kaplan-Meier analysis and Cox proportional hazards regression models were used to investigate the correlation between TROP2 expression and prognosis of GBC patients. Kaplan-Meier analysis indicated that patients with high TROP2 expression had poor overall survival (P<0.001). Multivariate analysis showed that high TROP2 expression was an independent predictor of overall survival. In conclusion, our data suggest for the first time that the increased expression of TROP2 in GBC is associated significantly with aggressive progression and poor prognosis. In conclusion, this study confirmed that TROP2 might be involved in regulating the EMT and malignant progression in GBC. It also provided the first evidence that TROP2 expression in GBC was an independent prognostic factor of patients, which might be a potential diagnostic and therapeutic target of GBC.

Identification of matrix-remodeling associated 5 as a possible molecular oncotarget of pancreatic cancer.

Pancreatic cancer has an extremely poor prognosis. Here we examined expression, potential functions and underlying mechanisms of MXRA5 (matrix remodeling associated 5) in pancreatic cancer. Bioinformatics studies revealed that MXRA5 transcripts are significantly elevated in pancreatic cancer tissues, correlating with the poor overall survival, high T-stage, N1 and pathologic stage of the patients. MXRA5 mRNA and protein expression is significantly elevated in microarray pancreatic cancer tissues and different pancreatic cancer cells. In primary and immortalized (BxPC-3 and PANC-1 lines) pancreatic cancer cells, shRNA-induced MXRA5 silencing or CRISPR/Cas9-mediated MXRA5 knockout suppressed cell survival, proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT), while provoking cell apoptosis. Conversely, forced overexpression of MXRA5 further promoted pancreatic cancer cell progression and EMT. Bioinformatics studies and the protein chip analyses revealed that differentially expressed genes (DEGs) and differentially expressed proteins (DEPs) in MXRA5-overexpressed primary pancreatic cancer cells were enriched in the PI3K-Akt-mTOR cascade. Indeed, Akt-mTOR activation in primary human pancreatic cancer cells was inhibited by MXRA5 shRNA or knockout, but was augmented following MXRA5 overexpression. In vivo, the growth of MXRA5 KO PANC-1 xenografts was largely inhibited in nude mice. Moreover, intratumoral injection of adeno-associated virus-packed MXRA5 shRNA potently inhibited primary pancreatic cancer cell growth in nude mice. Akt-mTOR activation was also largely inhibited in the MXRA5-depleted pancreatic cancer xenografts. Contrarily MXRA5 overexpression promoted primary pancreatic cancer cell growth in nude mice. Together, overexpressed MXRA5 is important for pancreatic cancer cell growth possibly through promoting EMT and Akt-mTOR activation. MXRA5 could be a potential therapeutic oncotarget for pancreatic cancer.

Perifosine sensitizes curcumin-induced anti-colorectal cancer effects by targeting multiple signaling pathways both in vivo and in vitro.

Our study shows that coadministration of curcumin and an orally bioactive alkylphospholipid perifosine results in a significant increase in colorectal cancer cell apoptosis and a marked inhibition of cell growth both in vitro and in vivo. This novel combinatorial regimen leads to changes of multiple cell signaling pathways including inactivation of Akt and nuclear factor-κB as well as activation of c-Jun N-terminal kinases and endoplasmic reticulum stress. Further, perifosine and curcumin synergistically increase intracellular level of reactive oxygen species and ceramide, and downregulate the expression of cyclin D1 and Bcl-2 in colorectal cancer cells. These changes at molecular level together account for the cancer cell apoptosis and growth inhibition. We conclude that perifosine sensitizes colorectal cancer cells to curcumin by modulating multiple signaling pathways. Adding perifosine with curcumin may represent an effective therapy regimen against colorectal cancers, and possible other aggressive tumors.

The association between polymorphisms in the leptin receptor gene and risk of breast cancer: a systematic review and pooled analysis.

Many epidemiological studies have found that leptin correlates to body fat extent and breast cancer. Leptin exerts its physiological action through the leptin receptor (LEPR). However, published data on the association between LEPR alleles and breast cancer occurrence have led to in contradictory results. A total of 10 studies were identified to the meta-analysis, including 4,644 cases and 5,485 controls for LEPR rs1137101 polymorphism, 5 studies with 2,759 cases and 4,464 controls for rs1137100 polymorphism, and 2 studies for rs8051542, rs8051542, and rs8051542 polymorphisms. The pooled odds ratios (OR) with 95 % confidence intervals (CI) for breast cancer risk associated with LEPR genotypes were estimated. Elevated breast cancer risk was associated with LEPR rs1137101 polymorphism when all studies were pooled in the meta-analysis (allele contrast model: OR = 0.71, 95 % CI = 0.551-0.997). In the stratified analysis by ethnicity, significantly increased risks were also found among Asians for allele contrast model (OR 0.414, 95 % CI 0.312-0.550) and dominant model (OR 0.537, 95 % CI 0.370-0.781); for Africans, significantly increased risks were also found for allele contrast model (OR 0.716, 95 % CI 0.595-0.861), homozygote codominant (OR 0.537, 95 % CI 0.370-0.781) and dominant model (OR 1.595, 95 % CI 1.207-2.108). And significantly elevated breast cancer risk was associated with LEPR rs1137100 polymorphism for allele contrast (OR = 0.666, 95 % CI = 0.603-0.720) and homozygote codominant models (OR = 0.344, 95 % CI = 0.282-0.421). For LEPR rs8179183, rs4655537, and rs3762274 polymorphisms, no significant associations were detected in all comparison models. This pooled analysis suggested that rs1137101 and rs1137100 polymorphisms were significantly correlated with breast cancer risk and the A allele of LEPR rs1137101 variant and the G allele of LEPR rs1137100 variant were low-penetrant risk factors for developing breast cancer. Further, no significant associations existed between LEPR rs8179183, rs4655537, and rs3762274 polymorphisms and risk of breast cancer.

Prognostic Nutritional Index Predicts Outcome of PD-L1 Negative and MSS Advanced Cancer Treated with PD-1 Inhibitors.

Purpose: Tumor mutational burden (TMB), microsatellite instability-high (MSI-H), and expression of programmed death ligand-1 (PD-L1) have emerged as predictive biomarkers for responsiveness to immune checkpoint inhibitors (ICIs) in several cancer types. However, for patients with negative PD-L1 expression, or microsatellite stability (MSS), some cases may experience favorable response to immunotherapy, and there is currently a lack of good relevant predictors. We tried to introduce several peripheral blood markers for predicting treatment outcome and immune-related adverse events (irAEs) in PD-L1 negative and MSS patients. Methods: A retrospective study of 142 PD-L1 negative and MSS patients was carried out. The association of peripheral blood markers including lactate dehydrogenase (LDH), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), albumin-to-globulin ratio (AGR), prognostic nutrition index (PNI), and other factors with clinicopathological characters and prognosis were assessed by Cox regression and Kaplan-Meier methods. Results: Lower level of PNI and poor performance status (ECOG score of 2) was correlated with significantly shorter overall survival (OS) and worse outcome of ICIs. The multivariate analysis revealed that PNI (for OS HR = 0.465, 95% CI: 0.236-0.916, p = 0.027; for PFS HR = 0.493, 95% CI: 0.251-0.936, p = 0.031) and ECOG score (for OS HR = 4.601, 95% CI: 2.676-7.910, p < 0.001; for PFS HR = 2.830, 95% CI: 1.707-4.691, p < 0.001) were independent prognostic factors for OS and PFS. NLR was related to the onset of irAEs. Conclusions: Pretreatment level of PNI and NLR, beyond PD-L1 expression and MSS, can improve the predictive accuracy for immunotherapy outcomes and has the potential to expand the candidate pool of patients for treatment with ICIs.

The bevacizumab plus oxaliplatin-based chemotherapy regimen is more suitable for metastatic colorectal cancer patients with a history of schistosomiasis: a clinical retrospective analysis.

Background: The basic platelet counts of schistosomiasis patients are low. If it does not meet the requirements for chemotherapy, the patient's treatment will not be carried out, which directly affects their prognosis. Therefore the impact of treatment on platelet counts is critically important. The effects of bevacizumab plus oxaliplatin-based chemotherapy and bevacizumab plus irinotecan-based chemotherapy regimens on platelets are different but have not been determined. In order to find a more suitable plan for metastatic colorectal cancer (mCRC) patients with a history of schistosomiasis, we conducted a retrospective analysis of mCRC patients and evaluated the impact of bevacizumab on their platelets. Methods: The medical records of all mCRC patients with a history of schistosomiasis who received oxaliplatin-based chemotherapy or irinotecan-based chemotherapy as first-line treatment for no less than 4 cycles, with or without bevacizumab from September 1, 2017, to June 30, 2019, in Kunshan Hospital were reviewed. Six-month cumulative incidence rates of splenomegaly and thrombocytopenia of chemotherapy with and without bevacizumab groups, oxaliplatin-based chemotherapy with and without bevacizumab groups, irinotecan-based chemotherapy with and without bevacizumab groups were compared from the first cycle until the completion of chemotherapy using Kaplan-Meier analysis and Log-rank test. Results: Evaluable splenic enlargement and thrombocytopenia results were obtained from 153 mCRC patients. The 6-month cumulative incidence rates of splenomegaly (23.3% vs. 55%; P=0.01) and that of thrombocytopenia (43.8% vs. 57.5%; P=0.40) were lower in the bevacizumab group than the non-bevacizumab group, however there were no statistical differences for the rates of thrombocytopenia. For patients treated with oxaliplatin, the rates of splenomegaly (19.5% vs. 66.7%; P=0.01) and thrombocytopenia (31.7% vs. 77.2%; P=0.02) were lower in the bevacizumab-treated cohort than that in the non-bevacizumab cohort. When stratified for irinotecan, there were no statistical differences in the frequency of splenomegaly between the two groups. However, the rates of thrombocytopenia were higher in the bevacizumab-treated cohort than that in the non-bevacizumab cohort (59.4% vs. 8.7%; P=0.01). Conclusions: The bevacizumab plus oxaliplatin-based chemotherapy regimen is safer for mCRC patients with a history of schistosomiasis, especially for patients with a lower platelet count.

Gross perianal embryonal rhabdomyosarcoma with severe multiple bone metastases throughout the body: a case report.

In adults, embryonal rhabdomyosarcoma (ERMS) is rare and has a poor prognosis. Giant perianal ERMS with severe multiple bone metastases at initial diagnosis has not been reported and lacks effective treatment options. This current case report describes a 31-year-old female patient that presented with a large lump on the right side of the anus. ERMS was diagnosed, accompanied by multiple bone metastases throughout the body and severe thrombocytopenia. She had an extremely low platelet count at initial diagnosis, making systemic chemotherapy inappropriate. Genetic testing did not help identify effective targeted drugs. A multi-target tyrosine kinase inhibitor, anlotinib, was selected to control the tumours combined with local radiotherapy to relieve pain. The lump became smaller and this reduction was maintained for 5 months. At 7 months after the diagnosis, the patient died of thrombocytopenia. This current case may provide supportive evidence for a potential treatment for patients with advanced ERMS, especially those not suitable for chemotherapy or surgery.

The sphingosine kinase inhibitor SKI-V suppresses cervical cancer cell growth.

Overexpression and/or overactivation of sphingosine kinase 1/2 (SphK1/2) is important for tumorigenesis and progression of cervical cancer. The current study examined the potential activity and signaling mechanisms of SKI-V, a non-lipid small molecule SphK inhibitor, against cervical cancer cells. In different primary and immortalized cervical cancer cells, SKI-V exerted significant anti-cancer activity by inhibiting cell viability, colony formation, proliferation, cell cycle progression and cell migration. Significant apoptosis activation was detected in SKI-V-treated cervical cancer cells. Significantly, SKI-V also provoked programmed necrosis cascade in cervical cancer cells, as it induced mitochondrial p53-cyclophilin-D-adenine nucleotide translocator-1 (ANT1) complexation, mitochondrial membrane potential collapse, reactive oxygen species production and the release of lactate dehydrogenase into the medium. Further, SKI-V blocked SphK activation and induced ceramide accumulation in primary cervical cancer cells, without affecting SphK1/2 expression. SKI-V-induced cytotoxicity in cervical cancer cells was largely inhibited by sphingosine-1-phosphate or the SphK1 activator K6PC-5, but was sensitized by adding the short-chain ceramide C6. Moreover, SKI-V inhibited Akt-mTOR (mammalian target of rapamycin) activation in primary cervical cancer cells, and its cytotoxicity was mitigated by a constitutively-active Akt. In vivo, daily intraperitoneal injection of SKI-V significantly inhibited subcutaneous primary cervical cancer xenograft growth in nude mice. Together, the SphK inhibitor SKI-V suppresses cervical cancer growth in vitro and in vivo.

Identification of Gαi3 as a promising target for osteosarcoma treatment.

Sustained activation of multiple receptor tyrosine kinases (RTKs) simultaneously is vital for tumorigenesis and progression of osteosarcoma (OS). Gαi proteins recruitment to various RTKs mediates downstream oncogenic signaling activation. The expression, functions and underlying mechanisms of Gαi3 in human OS were examined. Expression of Gαi3 is robustly elevated in human OS tissues and is correlated with a poor overall survival. In patient-derived primary OS cells and immortalized lines (MG63 and U2OS), Gαi3 depletion, by shRNA and CRISPR/Cas9 strategies, robustly suppressed cell viability, proliferation and migration, while provoking G1-S arrest and apoptosis activation. Conversely, Gαi3 overexpressing ectopically can accelerate proliferation and migration of OS cells. In OS cells, Gαi3 immunoprecipitated with VEGFR2, FGFR, PGDFR and EGFR, mediating downstream cascade transduction. Akt-mTOR activation in primary OS cells was potently inhibited by Gαi3 shRNA, knockout or dominant negative mutation, but augmented after Gαi3 overexpression. In vivo studies showed that Gαi3 shRNA AAV (adeno-associated viruses) intratumoral injection largely inhibited the growth of subcutaneous xenografts of primary OS cells. Moreover, the growth of the Gαi3-knockout primary OS xenografts was much slower than that of OS xenografts with empty vector. In Gαi3-depleted OS xenografts tissues, Gαi3 downregulation and Akt-mTOR inactivation were detected. Taken together, overexpressed Gαi3 mediates RTK-Akt signaling to drive OS progression.

Bioinformatics analysis and experimental verification of the prognostic and biological significance mediated by fatty acid metabolism related genes for hepatocellular carcinoma.

Background: Liver cancer is among the leading causes of death related to cancer around the world. The most frequent type of human liver cancer is hepatocellular carcinoma (HCC). Fatty acid (FA) metabolism is an emerging hallmark that plays a promoting role in numerous malignancies. This study aimed to discover a FA metabolism-related risk signature and formulate a better model for HCC patients' prognosis prediction. Methods: We collected mRNA expression data and clinical parameters of patients with HCC using the TCGA databases, and the differential FA metabolism-related genes were explored. To create a risk prognostic model, we carried out the consensus clustering as well as univariate and multivariate Cox regression analyses. 16 genes were used to establish a prognostic model, which was then validated in the ICGC dataset. The accuracy of the model was performed using receiver operating characteristic (ROC) analyses, decision curve analysis (DCA) and nomogram. The immune cell infiltration level of risk genes was evaluated with single-sample GSEA (ssGSEA) algorithm. To reflect the response to immunotherapy, immunophenoscore (IPS) was obtained from TCGA-LIHC. Then, the expression of the candidate risk genes (p < 0.05) was validated by qRT-PCR, Western blotting and single-cell transcriptomics. Cellular function assays were performed to revealed the biological function of HAVCR1. Results: According to the TCGA-LIHC cohort analysis, the majority of the FA metabolism-related genes were expressed differentially in the HCC and normal tissues. The prognosis of patients with high-risk scores was observed to be worse. Multivariate COX regression analysis confirmed that the model can be employed as an independent prognosis factor for HCC patients. Furthermore, ssGSEA analysis revealed a link between the model and the levels of immune cell infiltration. Our model scoring mechanism also provides a high predictive value in HCC patients receiving anti-PDL1 immunotherapy. One of the FA metabolism-related genes, HAVCR1, displays a significant differential expression between normal and HCC cell lines. Hepatocellular carcinoma cells (Huh7, and HepG2) proliferation, motility, and invasion were all remarkably inhibited by HAVCR1 siRNA. Conclusion: Our study identified a novel FA metabolism-related prognostic model, revealing a better potential treatment and prevention strategy for HCC.

The requirement of phosphoenolpyruvate carboxykinase 1 for angiogenesis in vitro and in vivo.

We here examined the potential biological function of phosphoenolpyruvate carboxykinase 1 (PCK1) in angiogenesis. shRNA- or CRISPR-Cas9-induced PCK1 depletion potently inhibited endothelial cell proliferation, migration, sprouting, and tube formation, whereas ectopic PCK1 overexpression exerted opposite activity. In HUVECs, Gαi3 expression and Akt activation were decreased following PCK1 depletion, but were augmented by ectopic PCK1 overexpression. In vivo, retinal expression of PCK1 gradually increased from postnatal day 1 (P1) to P5. The intravitreous injection of endothelial-specific PCK1 shRNA adenovirus at P1 potently inhibited the radial extension of vascular plexus at P5. Conditional endothelial knockdown of PCK1 in adult mouse retina increased vascular leakage and the number of acellular capillaries while decreasing the number of RGCs in murine retinas. In diabetic retinopathy patients, PCK1 mRNA and protein levels were up-regulated in retinal tissues. Together, PCK1 is essential for angiogenesis possibly by mediating Gαi3 expression and Akt activation.

Activation of AMP-activated protein kinase is involved in vincristine-induced cell apoptosis in B16 melanoma cell.

The molecular basis for induction of apoptosis in melanoma cells by vincristine remains unknown. Here we tested the potential involvement of AMP-activated protein kinase (AMPK) in this process. We found for the first time that vincristine induces AMPK activation (AMPKα, Thr 172) and Acetyl-CoA carboxylase (ACC, Ser 79) (a downstream molecular target of AMPK) phosphorylation in cultured melanoma cells in vitro. Reactive oxygen species (ROS) dependent LKB1 activation serves as the upstream signal for AMPK activation. AMPK inhibitor (compound C) or AMPKα siRNA knockdown inhibits vincristine induced B16 melanoma cell apoptosis, while AMPK activator 5-aminoimidazole-4-carboxamide-1-ß-riboside (AICAR) enhances it. AMPK activation is involved in vincristine induced p53 phosphorylation and stabilization, the latter is known to mediate melanoma cell apoptosis. Further, activation of AMPK by vincristine inhibits mTOR Complex 1 (mTORC1) in B16 melanoma cells, which serves as another important mechanism to induce melanoma cell apoptosis. Our study provides new insights into understanding the cellular and molecular mechanisms of vincristine induced cancer cell death/apoptosis. We suggest that combining AMPK activator AICAR with vincristine may have potential to be used as a new therapeutic intervention against melanoma.

Association between polymorphisms of trinucleotide repeat containing 9 gene and breast cancer risk: evidence from 62,005 subjects.

Trinucleotide repeat containing 9 (TNRC9) is a gene located at chromosome 16q12. Although of an uncertain function, it is a newly described risk factor for breast cancer. It contains a putative high-mobility group box motif, suggesting its possible role as transcription factor; it has been implicated in breast cancer metastasis. Published studies on the association between TNRC9 polymorphisms and breast cancer risk remain inconclusive, and a meta-analysis is required to verify the association. This pioneering research performed a meta-analysis of eight studies comprising a total of 25,828 cases and 36,177 controls. Significantly elevated breast cancer risk was associated with TNRC9 rs3803662 polymorphism when all studies were pooled in the meta-analysis (T vs. C allele contrast model: OR 1.18, 95% CI 1.09-1.28; TT vs. CC homozygote codominant model: OR 1.26, 95% CI 1.02-1.55; TT vs. CC+CT recessive model: OR 1.23, 95% CI 1.06-1.42). For TNRC9 rs12443621 polymorphism, no significant association was detected in all genetic models. For TNRC9 rs12443621 polymorphism, meanwhile, no significant association was observed in all comparison models. Conclusively, this meta-analysis suggests that TNRC9 rs3803662 polymorphism was significantly correlated with breast cancer risk and the variant T allele of TNRC9 rs3803662 polymorphism is a low-penetrant risk factor for developing breast cancer. There is no significant association between TNRC9 rs12443621 and rs8051542 polymorphisms and risk of breast cancer in current literature.

Association between polymorphisms of the ataxia telangiectasia mutated gene and breast cancer risk: evidence from the current studies.

Epidemiological studies have evaluated the association between ataxia telangiectasia mutated (ATM) gene polymorphisms and breast cancer risk. However, published data are still inconclusive. We performed a meta-analysis for the first time, based on currently available evidence, by searching PubMed, ISI Web of Knowledge, and Embase databases to derive a more precise assessment of the relationship. Following the inclusion and exclusion criteria, nine publications were included in this meta-analysis. Of these studies, one had a deviation from the Hardy-Weinberg equilibrium (HWE) at a statistical significance level of 0.01 in controls, and another two had no available data for HWE. We observed that the ATM 5557G>A polymorphism was significantly correlated with breast cancer risk when all studies were pooled into the meta-analysis (recessive model: odds ratio, OR = 0.67; 95% confidence interval (CI) 0.51-0.89). For the ATM IVS38-8T>C polymorphism, no significant association was found in the allele contrast, heterozygote codominant, and dominant models. There were no available data to perform this meta-analysis in the homozygote codominant and recessive models. For the ATM IVS1+19A>T polymorphism, a significant association with breast cancer risk was found in the allele contrast model (C vs. T: OR = 1.60; 95% CI 1.02-2.52). For the IVS34+60G>A polymorphism, no significant association was found in the allele contrast, codominant, dominant, and recessive models. Egger's test did not suggest any evidence of publication bias (P = 0.47 for the recessive model). In conclusion, there is limited evidence to indicate that ATM polymorphisms are associated with increased risk of breast cancer.