Tyrosine phosphatase SHP2 aggravates tumor progression and glycolysis by dephosphorylating PKM2 in gastric cancer.

Gastric cancer (GC) is among the most lethal human malignancies, yet it remains hampered by challenges in fronter of molecular-guided targeted therapy to direct clinical treatment strategies. The protein tyrosine phosphatase Src homology 2 domain-containing phosphatase 2 (SHP2) is involved in the malignant progression of GC. However, the detailed mechanisms of the posttranslational modifications of SHP2 remain poorly understood. Herein, we demonstrated that an allosteric SHP2 inhibitor, SHP099, was able to block tumor proliferation and migration of GC by dephosphorylating the pyruvate kinase M2 type (PKM2) protein. Mechanistically, we found that PKM2 is a bona fide target of SHP2. The dephosphorylation and activation of PKM2 by SHP2 are necessary to exacerbate tumor progression and GC glycolysis. Moreover, we demonstrated a strong correlation between the phosphorylation level of PKM2 and adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) in GC cells. Notably, the low phosphorylation expression of AMPK was negatively correlated with activated SHP2. Besides, we proved that cisplatin could activate SHP2 and SHP099 increased sensitivity to cisplatin in GC. Taken together, our results provide evidence that the SHP2/PKM2/AMPK axis exerts a key role in GC progression and glycolysis and could be a viable therapeutic approach for the therapy of GC.

Genomic analysis of hypoxia and mitophagy related genes with prognosis and characterization of the immune microenvironment in LUAD.

Background: Lung adenocarcinoma (LUAD) stands as a prominent subtype within the realm of non-small cell lung cancer and constitutes a primary contributor to cancer-related mortality on a global scale. Notably, hypoxia, a prevalent attribute within solid tumor environments, and mitophagy, a selective manifestation of autophagy dedicated to the removal of damaged mitochondria, have risen to prominence as pivotal factors influencing the initiation and advancement of tumorigenesis. Methods: This investigation harnessed publicly accessible genomic datasets encompassing LUAD patients to delineate genes linked to hypoxia and mitophagy, termed hereafter as hypoxia and mitophagy-related genes (HMRGs). Large-scale repositories furnished both gene expression profiles and clinical particulars. The expression profiles of HMRGs were meticulously scrutinized across 1,093 LUAD specimens, leveraging resources such as The Cancer Genome Atlas and Gene Expression Omnibus datasets. A methodical exploration of HMRG patterns within LUAD led to the discernment of two distinct molecular subtypes. Moreover, a discernible correlation emerged between the subtypes and their respective clinical attributes. A risk scoring system was formulated to prognosticate overall survival (OS) and therapeutic responsiveness in LUAD patients. Subsequently, the reliability of this scoring system was authenticated, and a nomogram was adopted to refine the clinical utility range of the risk score. The proliferation and migration impacts of KRT8 on LUAD cells were evaluated through cck8 assays, edu assays, and transwell assays, the results were further validated in vivo. Results: Elevated risk scores were indicative of unfavorable OS probabilities. Furthermore, these risk scores exhibited associations with immune checkpoints and chemotherapeutic drug sensitivity. Collectively, our exhaustive analysis of HMRGs in LUAD patients unveiled their conceivable participation in configuring the multifaceted tumor microenvironment, encompassing clinicopathological attributes and prognosis. A sequence of experiments illuminated the pro-proliferative and pro-migratory attributes of KRT8 in vitro and vivo, thus underscoring its carcinogenic potential. Conclusions: In this study, we have unearthed innovative gene signatures tethered to HMRGs, which harbor prognostic implications concerning patient outcomes. These insights hold potential for steering the development of targeted therapeutic modalities tailored for LUAD.

Modelling and predicting online vaccination views using bow-tie decomposition.

Social media has become increasingly important in shaping public vaccination views, especially since the COVID-19 outbreak. This paper uses bow-tie structure to analyse a temporal dataset of directed online social networks that represent the information exchange among anti-vaccination, pro-vaccination and neutral Facebook pages. Bow-tie structure decomposes a network into seven components, with two components, strongly connected component (SCC) and out-periphery component (OUT), emphasized in this paper: SCC is the largest strongly connected component, acting as an 'information magnifier', and OUT contains all nodes with a directed path from a node in SCC, acting as an 'information creator'. We consistently observe statistically significant bow-tie structures with different dominant components for each vaccination group over time. In particular, the anti-vaccination group has a large OUT, and the pro-vaccination group has a large SCC. We further investigate changes in opinions over time, as measured by fan count variations, using agent-based simulations and machine learning models. Across both methods, accounting for bow-tie decomposition better reflects information flow differences among vaccination groups and improves our opinion dynamics prediction results. The modelling frameworks we consider can be applied to any multi-stance temporal network and could form a basis for exploring opinion dynamics using bow-tie structure in a wide range of applications.

The microprotein encoded by exosomal lncAKR1C2 promotes gastric cancer lymph node metastasis by regulating fatty acid metabolism.

Lymph node metastasis (LNM) is the prominent route of gastric cancer dissemination, and usually leads to tumor progression and a dismal prognosis of gastric cancer. Although exosomal lncRNAs have been reported to be involved in tumor development, whether secreted lncRNAs can encode peptides in recipient cells remains unknown. Here, we identified an exosomal lncRNA (lncAKR1C2) that was clinically correlated with lymph node metastasis in gastric cancer in a VEGFC-independent manner. Exo-lncAKR1C2 secreted from gastric cancer cells was demonstrated to enhance tube formation and migration of lymphatic endothelial cells, and facilitate lymphangiogenesis and lymphatic metastasis in vivo. By comparing the metabolic characteristics of LN metastases and primary focuses, we found that LN metastases of gastric cancer displayed higher lipid metabolic activity. Moreover, exo-lncAKR1C2 encodes a microprotein (pep-AKR1C2) in lymphatic endothelial cells and promotes CPT1A expression by regulating YAP phosphorylation, leading to enhanced fatty acid oxidation (FAO) and ATP production. These findings highlight a novel mechanism of LNM and suggest that the microprotein encoded by exosomal lncAKR1C2 serves as a therapeutic target for advanced gastric cancer.

Plasma heat shock protein 90alpha as a biomarker for the diagnosis of liver cancer: in patients with different clinicopathologic characteristics.

PURPOSES: The purposes of this study were to assess the correlation between the plasma level of Hsp90α and the clinicopathological characteristics of patients with liver cancer and compare the diagnostic efficacy of Hsp90α, AFP, CEA, and CA199 in HCC. EXPERIMENTAL DESIGN: A total of 200 individuals, including 140 patients with liver cancer or benign liver diseases and 60 healthy people, were enrolled for quantitative measurement of plasma Hsp90α by ELISA. RESULTS: The plasma level of Hsp90α was significantly different between patients with liver cancer or benign liver diseases and healthy controls (P < 0.001). The sensitivity, specificity, and AUC (95% CI) of Hsp90α were 93.2%, 85.4%, and 0.931% (0.891-0.972%), respectively, when Hsp90α was applied to differentiate liver cancer patients and healthy controls. Significant positive correlations between the plasma Hsp90α level and clinicopathological characteristics such as the history of basic liver disease (P = 0.038), active stage of hepatitis (P = 0.039), Child-Pugh score (P < 0.001), size of focal liver lesions (P = 0.004), and extrahepatic metastasis (P < 0.001) were observed. AFP + Hsp90α was the best combination strategy for the auxiliary diagnosis of HCC, with a sensitivity of 95.7%, a specificity of 97.5%, and an AUC of 0.990 (0.976-1.000). The level of plasma Hsp90α decreased significantly (P < 0.001) after resection of tumor tissue. CONCLUSIONS: This study demonstrated that plasma Hsp90α levels are useful as a diagnostic biomarker in liver cancer and may predict the responses of patients with liver cancer to surgery. Some clinicopathological characteristics could affect the plasma Hsp90α levels.

Serum microRNAs as Biomarkers for the Noninvasive Early Diagnosis of Biliary Tract Cancer.

BACKGROUND: Biliary tract cancers (BTCs) are aggressive malignancies with difficult early diagnosis and poor prognosis. Studies have shown that microRNAs (miRNAs) are expected to be biomarkers of the disease, which indicates that we can diagnose cancers according to the miRNAs that have significant changes. The aim of this study was to explore miRNA biomarkers of BTCs. METHODS: A total of 163 samples were collected and divided into the control group, the benign group and the malignant group. High-throughput low-density chips were used to screen miRNAs with significant changes. Then, the preliminary screening test and the verification test were performed by quantitative real time PCR (qRT-PCR). Finally, the level of miRNAs in serum exosomes was measured. RESULTS: MiR-10a, miR-21, miR-135b, miR-221, and miR-214 were upregulated in the BTCs group compared to the control group. The change in the miR-221 level was statistically significant when the malignant group was compared with the benign group (P<0.01). Meanwhile, miR-135b and miR-214 were enriched in serum exosomes. CONCLUSION: Five miRNAs in the serum were found to be significantly upregulated in patients with BTCs. Among them, miR-221 can serve as an early diagnostic marker for BTCs patients. MiR-10a, miR-21, miR-135b and miR-214 can be used as biomarkers for the diagnosis of biliary diseases.

Serum miR-185 Is a Diagnostic and Prognostic Biomarker for Non-Small Cell Lung Cancer.

OBJECTIVE: MicroRNAs (miRNAs) have been found to play important roles in the development of non-small cell lung carcinoma (NSCLC). The aim of this study was to analyze the expression and clinical value of serum miR-185 in NSCLC. METHODS: Serum miR-185 levels were detected in 146 NSCLC patients, 50 patients with carcinoma in situ, 25 patients with non-malignant lung diseases (NMLD), and 80 healthy controls using quantitative reverse transcription PCR. The correlation between serum miR-185 level and clinical status of NSCLC was explored. RESULTS: The results revealed that serum miR-185 expression was progressively decreased in healthy controls, patients with NMLD, patients with carcinoma in situ and NSCLC patients. In addition, compared to carcinoembryonic antigen (CEA), serum miR-185 demonstrated better diagnostic accuracy for discriminating patients with carcinoma from healthy controls, NSCLC patients from healthy controls and NSCLC patients from patients with carcinoma in situ. In addition, serum miR-185 levels were significantly elevated in post-treated samples compared to the pre-treated samples. Moreover, reduced serum miR-185 was closely associated with unfavorable clinicopathological parameters and worse survival. Univariate and multivariate cox regression analysis confirmed that serum miR-185 was an independent prognostic indicator for NSCLC. CONCLUSIONS: Collectively, our findings have demonstrated that serum miR-185 might serve as a promising and robust biomarker for the early detection and prognosis prediction of NSCLC.

MicroRNA-155 promotes gastric cancer growth and invasion by negatively regulating transforming growth factor-ß receptor 2.

Gastric cancer (GC) is one of the most common malignancies worldwide and has high morbidity and mortality rates. It is essential to elucidate the molecular events of GC proliferation and invasion, which will provide new therapeutic targets for GC. The inactivation of transforming growth factor-ß receptor 2 (TGFßR2) correlates with cancer cell growth and metastasis, but the mechanisms underlying the downregulation of TGFßR2 expression remain unknown. MicroRNAs (miRNAs) act as post-transcriptional regulators and play a key role in the development of cancers. Bioinformatics analysis and luciferase reporter assays have shown that miR-155 directly binds to the 3'-UTR of TGFßR2 mRNA. In this study, we found that the TGFßR2 protein levels, but not mRNA levels, were downregulated in GC tissues, and the levels of miR-155 were significantly increased in GC tissues. We deduced that miR-155 was inversely correlated with TGFßR2 in GC cells. In vitro studies showed that overexpression of miR-155 in SGC7901 inhibited the expression of TGFßR2 and then promoted GC cell proliferation and migration, whereas miR-155 inhibitor showed opposite effects. In addition, the tumor-suppressing function of TGFßR2 was verified by using siRNA and TGFßR2 overexpressing plasmids. The results showed that miR-155 promotes cell growth and migration by negatively regulating TGFßR2. Thus, miR-155-regulated TGFßR2 as a potential therapeutic target in GC.

MiR-520b/e Regulates Proliferation and Migration by Simultaneously Targeting EGFR in Gastric Cancer.

BACKGROUND: MicroRNAs (miRNAs) have been demonstrated to play a crucial role in tumorigenesis. Previous studies have shown that miR-520b/e acts as a tumor suppressor in several tumors. Other studies indicated that epidermal growth factor receptor (EGFR) is highly expressed in many tumors, and involved in the development of tumors, such as cell proliferation, migration, angiogenesis and apoptosis. However, the correlation of miRNAs and EGFR in gastric cancer (GC) has not been adequately investigated. Our aim was to explore the relationship. METHODS: The expression levels of EGFR and miR-520b/e were examined by RT-PCR and Western blot. We also investigated the relationship between EGFR and miR-520b/e in GC cell lines by relevant experiments. RESULTS: In this study, we found that miR-520b/e inhibits the protein expression of EGFR by directly binding with the 3'-untranslated region (3'-UTR). And it was shown that the down-regulation of miR-520b/e promotes cell proliferation and migration by negative regulation of the EGFR pathway, while over-expression of miR-520b/e inhibits these properties. In addition, the biological function of EGFR in GC cell lines was validated by silencing and over-expression assays respectively. CONCLUSIONS: Taken together, our results demonstrate that miR-520b/e acts as a tumor suppressor by regulating EGFR in GC, and provide a novel marker and insight for the potential therapeutic target of GC.

The mitochondrial folylpolyglutamate synthetase gene is required for nitrogen utilization during early seedling development in arabidopsis.

Investigations into the biochemical processes and regulatory mechanisms of nitrogen (N) utilization can aid in understanding how N is used efficiently in plants. This report describes a deficiency in N utilization in an Arabidopsis (Arabidopsis thaliana) transfer DNA insertion mutant of the mitochondrial folylpolyglutamate synthetase gene DFC, which catalyzes the conjugation of glutamate residues to the tetrahydrofolate during folate synthesis. The mutant seedlings displayed several metabolic changes that are typical of plant responses to low-N stress, including increased levels of starch and anthocyanin synthesis as well as decreased levels of soluble protein and free amino acid, as compared with those in wild-type seedlings when external N was sufficient. More striking changes were observed when dfc seedlings were grown under N-limited conditions, including shorter primary roots, fewer lateral roots, higher levels of glycine and carbon-N ratios, and lower N content than those in wild-type seedlings. Gene expression studies in mutant seedlings revealed altered transcript levels of several genes involved in folate biosynthesis and N metabolism. The biochemical and metabolic changes also suggested that N assimilation is drastically perturbed due to a loss of DFC function. The observation that elevated CO(2) partly rescued the dfc phenotypes suggests that the alterations in N metabolism in dfc may be mainly due to a defect in photorespiration. These results indicate that DFC is required for N utilization in Arabidopsis and provide new insight into a potential interaction between folate and N metabolism.