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Background: Anti‐PD1/PD‐L1 antibody plus human epidermal growth factor receptor 2 (HER2) antibody and chemotherapy have become the new first‐line therapy for HER2 overexpression‐positive advanced gastric cancers (GC), suggesting that HER2 and PD‐L1 play a vital role in guiding systemic treatment for patients with GC. This study aimed to depict the genomic and immune landscapes of Chinese patients with GC and investigate their correlations with HER2 amplification and PD‐L1 expression. Patients and Methods: Next‐generation targeted sequencing and PD‐L1 immunohistochemistry were performed on tumor samples from 735 patients with pathologically diagnosed GC. The genomic and immune landscapes and their correlations with HER2 amplification and PD‐L1 expression were analyzed. Results: The most commonly mutated genes in Chinese GC were TP53 (64%), CDH1 (20%), ARID1A (18%), HMCN1 (15%), KMT2D (11%), and PIK3CA (11%). Seventy‐six (10%) patients were HER2 amplification, and 291 (40%) had positive PD‐L1 expression. Classifying the total population based on HER2 amplification and PD‐L1 expression level, 735 patients were divided into four subgroups: HER2+/PD‐L1+ (4.5%), HER2+/PD‐L1− (5.9%), HER2−/PD‐L1+ (35.1%), and HER2−/PD‐L1− (54.5%). The HER2+/PD‐L1− and HER2+/PD‐L1+ subgroups exhibited dramatically higher rate of TP53 mutations, CCNE1 and VEGF amplifications. The HER2+/PD‐L1− subgroup also had a markedly higher rate of MYC amplification and KRAS mutations. The HER2−/PD‐L1+ subgroup had significantly higher rate of PIK3CA mutations. HER2+/PD‐L1− subgroup had the highest TMB level and HER2−/PD‐L1+ subgroup had the highest proportion of patients with microsatellite instability‐high than other subgroups. Furthermore, we observed that different HER2 amplification levels had distinct impacts on the correlations between PD‐L1 expression and therapeutic genomic alterations, but no impact on the prognosis. Conclusion: The combination of HER2 amplification and PD‐L1 expression in Chinese patients with GC could stratify the total populations into several subgroups with distinctive genomic and immune landscapes, which should be considered when making personalized treatment decisions. [ABSTRACT FROM AUTHOR]

Objectives: Colorectal cancer (CRC), one of the most aggressive gastrointestinal malignancies, is a frequently diagnosed life-threatening cancer worldwide. Most CRC patients have poor prognosis mainly because of frequent metastasis and recurrence. Thus, it is crucial to find out some new biomarkers and to show deeper insights into the mechanisms of CRC. MLLT10, Myeloid/lymphoid or mixed-lineage leukemia translocated to 10, also known as AF10, a recurrent MLL partner. In this study, we found that MLLT10 promotes CRC tumor invasion and metastasis both in vitro and in vivo. Methods: Here, the expression of MLLT10 was evaluated by immunohistochemistry. Then, the plasmid and lentivirus particles for MLLT10 overexpression or knockdown were designed and constructed into SW620 and HT29 cells. Finally, cell proliferation assay, cell adhesion assay, transwell migration, and invasion assay were used to detect the migration and invasion ability of MLLT10 in CRC cells. A tail vein injection assay was employed to evaluate the role of MLLT10 in tumor metastases. Results: MLLT10 expression was significantly higher in CRC tissues than in noncancerous tissues and was associated with some clinicopathological factors. In vitro, the overexpression of MLLT10 promoted CRC cell migration and invasion, while after MLLT10 was knocked down, the opposite results were observed. Furthermore, we used animal metastasis models to detect the function of MLLT10 in vivo, the results are same with the outcomes in vitro. In lung metastasis sites, the knockdown of MLLT10 in SW620 cells significantly inhibited Vimentin expression, whereas the E-Cadherin was increased. Conclusions: These results indicate that MLLT10 regulates the metastasis of CRC cells via EMT. [ABSTRACT FROM AUTHOR]

Antimony selenide film doped with Zn2+ was deposited on ultra-white glass by hydrothermal method. The photocatalytic activity was evaluated by photocatalytic decolorization reaction with methylene blue (MB) solution. According to the free radical capture experiment, photogenerated holes (h+) and superoxide radicals (·O2−) are the decisive active substances in the photocatalytic process. [Display omitted] • Zn-doped Sb 2 Se 3 thin films prepared by hydrothermal deposition. • The amount of zinc doping is the key to the enhancement of photocatalytic activity. • The doping of Zn2+ increases the visible light absorbance of the Sb 2 Se 3 thin film. • Metal ion doping provides a simple method for metal selenide photocatalysts. Sb 2 Se 3 is a promising light-absorbing material with low cost and good photocatalytic activity. In this paper, Sb 2 Se 3 thin films doped with zinc (Zn) were deposited on ultra-white glass by hydrothermal method, using ZnCl 2 , sodium selenate and antimony potassium tartrate as raw materials. And the photocatalytic activity was evaluated by photocatalytic decolorization reaction with methylene blue (MB) solution. The results showed that the highest photocatalytic activity was displayed when Zn2+ was doped with 0.10 mmol, and its degradation rate of methylene blue was 1.66 times higher than that of pure Sb 2 Se 3. Zn2+ doped Sb 2 Se 3 film can effectively inhibit the recombination of electron-hole pairs, thereby improving the optical activity. According to the free radical capture experiment, photogenerated holes (h+) and superoxide radicals (·O2−) are the decisive active substances in the photocatalytic process. This method provides a reliable way for transition metal ions doped metal selenides to degrade organic dyes. [ABSTRACT FROM AUTHOR]

Tumor microenvironment (TME) (e.g., stromal cells) has been closely related to the pathological process of colorectal cancer (CRC). In TME, tumor-associated fibroblasts (CAFs) are the main stromal cells. The studies have showed that CAFs promoted tumor growth and metastasis in CRC and led to poor prognosis. Mounting evidence indicates that CAFs-mediated exosomes regulate the pathological process of neighboring tumor cells through the transmission of miRNAs. In our study, we aimed to explore the function of CAFs-derived exosome miR-181b-3p in CRC. First, the expression of miR-181b-3p in CRC was found to be up-regulated and its expression was dramatically up-regulated in CRC cells after co-incubation of CAFs-mediated exosomes with CRC cells. Then, it was found that the CAFs-derived exosomes were markedly enhanced the proliferation and migration of the CRC cells, and substantially reduced apoptosis. To elucidate the influence of CAFs-derived exosome miR-181b-3p on CRC, we overexpressed and knocked down the miR-181b-3p expression in CAFs, respectively. It was found that miR-181b-3p significantly increased the proliferation and migration of CRC cells. Furthermore, we conducted in vivo experiments. Finally, we demonstrated that CAF-derived exosome miR-181b-3p regulated sorting nexin 2 (SNX2) expression in CRC cells by bioinformatics prediction combined with luciferase reporter assay. Further cellular and animal experiments jointly elucidated that miR-181b-3p promoted the pathological process of CRC by SNX2 expression. In brief, our results demonstrated that CAFs-derived exosome miR-181b-3p promoted the pathogenesis of CRC by regulating SNX2 expression, which provides a novel idea for CRC treatment. • CAFs-derived exosome promotes the pathological process of CRC. • CAFs-derived exosome miR-181b-3p promotes the occurrence and development of CRC. • Exosomal miR-181b-3p promotes tumor growth by regulating SNX2-mediated ERK1/2 pathway. [ABSTRACT FROM AUTHOR]

Tumor cells surviving hypoxic stress acquire the ability to drive cancer progression. To explore the contribution of dehydrogenases to the low oxygen concentration response, we used siRNAs targeting 163 dehydrogenase‐coding genes and discovered that glutamate dehydrogenase 1 (GDH1) plays a critical role in regulating colorectal cancer (CRC) cell survival under hypoxia. We observed that GDH1 deficiency had an inhibitory effect on CRC occurrence and impaired hypoxia‐inducible factor 1‐alpha (HIF‐1α) stability even under hypoxia. Mechanistically, hypoxia triggered p300 recruitment to GDH1, promoting its acetylation at K503 and K527. GDH1 acetylation at K527 induced the formation of a GDH1 complex with EGLN1/HIF‐1α; in contrast, GDH1 acetylation at K503 reinforced its affinity for α‐ketoglutarate (αKG), and glutamate production. In line with this view, αKG is a product of GDH1 under normoxia, but hypoxia stimulation reversed GDH1 enzyme activity and αKG consumption by the EGLN1/HIF‐1α complex, increasing HIF‐1α stability and promoting CRC progression. Clinically, hypoxia‐modulated GDH1 AcK503/527 can be used as a biomarker of CRC progression and is a potential target for CRC treatment. Synopsis: This study identifies αKG metabolic enzyme glutamate dehydrogenase 1 (GDH1) as a major factor controling colorectal cancer (CRC) by facilitating HIF‐1a‐dependent cancer signaling. GDH1 is required for hypoxia response in CRC cells and associated with poor prognosis in patients.GDH1 depletion in the mouse intestine impairs CRC formation.Hypoxia‐induced acetylation of GDH1 by p300 is required for HIF‐1α stability.Hypoxia‐induced GDH1 acetylation at K503 reverses its dehydrogenase activity.Hypoxia‐induced GDH1 acetylation at K527 anchors GDH1 to the EGLN1/HIF‐1α complex.GDH1 acetylation is required for solid tumor formation and correlates with poor CRC prognosis. [ABSTRACT FROM AUTHOR]

Cerebral palsy (CP) is the most common childhood disability worldwide, yet biomarkers for predicting CP are lacking. By subjecting peripheral blood samples from 62 CP patients and 30 healthy controls to Affymetrix GeneChip ® PrimeView™ HumanGene Expression Microarray analysis, we identified the novel biomarker B-cell lymphoma 6 (BCL6) as the most upregulated gene in the CP samples. Gastrodin is a traditional Chinese medicine and bioactive compound that promotes adductor angle release, as well as gross and fine motor performance by increasing Gross Motor Function Measure-66 and Fine Motor Function Measure-45 scores. Gastrodin upregulates the mRNA expression of Mgl2 and Mrc1, M2 macrophage markers, and arginase activity, an M2 polarization indicator, in murine RAW264.7 macrophages. Moreover, these effects were blocked by BCL6 siRNA, which also abrogated the protective effects of Gastrodin against hydrogen peroxide-induced apoptosis and death in RAW264.7 cells. Our work identified BCL6 as a novel biomarker for early prediction of CP. Moreover, we demonstrated that Gastrodin not only stimulated polarization toward M2-like macrophages, which promote tissue repair, but also rescued macrophages from oxidative stress, apoptosis and death by inducing BCL6 expression. BCL6-targeted therapeutic strategies have promise for improving motor performance in CP patients. [ABSTRACT FROM AUTHOR]

Ovarian cancer (OC) is the leading cause of death for women diagnosed with gynecological cancer. Studies have shown that dysregulated miRNA expression is related to various cancers, including OC. Here, we aimed to explore the biological function and mechanism of miR-585-3p in the occurrence and development of OC. The expression level of miR-585-3p was found to be low in OC tissues and cells. We analyzed the biological function of miR-585-3p in OC through in vitro cell experiments. The results indicated that overexpression of miR-585-3p inhibited the proliferation, invasion, and migration of SW626 cells, while low expression of miR-585-3p had the opposite effect in SKOV3 cells. We then screened the target genes of miR-585-3p through miRDB database and detected the expression of target genes in OC cells. FSCN1 was found to be most significantly upregulated in OC cells. Dual-luciferase reporter assays revealed FSCN1 as a potential target of miR-585-3p. Western blot analysis showed that miR-585-3p targeted FSCN1 to inhibit protein phosphorylation of ERK. In vivo animal experiments also confirmed that miR-585-3p targets FSCN1 to inhibit tumor growth and block the MAPK signaling pathway. In summary, miR-585-3p inhibits the proliferation, migration, and invasion of OC cells by targeting FSCN1, and its mechanism of action may be achieved by inhibiting the activation of the MAPK signaling pathway. miR-585-3p may serve as a potential biomarker and therapeutic target for OC. [ABSTRACT FROM AUTHOR]

The role of lncRNAs in the regulation of glutamate metabolism and metabolic reprogramming of pancreatic cancer (PC) during nutrient deprivation is largely unknown. Our study found that alpha-ketoglutarate (aKG) levels were significantly reduced in the absence of XLOC_006390. We subsequently confirmed that the decrease in aKG was mainly due to the downregulation of glutamate dehydrogenase 1 (GDH1) at the mRNA level. Therefore, we first screened transcription factors targeting the GDH1 gene promoter and confirmed that c-Myc regulates GDH1 transcription. c-Myc binds to the promoter of GDH1 and activates its transcription. Downregulation of GDH1 mRNA levels by XLOC_006390 deletion could be rescued by overexpression of c-Myc. Overexpression of XLOC_006390 promoted the protein stability of c-Myc by blocking its ubiquitination. Clinically, XLOC_006390 was positively correlated with the mRNA level of GDH1, and c-Myc positively regulated GDH1 gene expression, which was tightly associated with PC patient prognosis. The dysregulated lncRNA/c-Myc axis increased glutamate metabolism, promoting PC progression to a higher stage. Therefore, XLOC_006390/c-Myc may be a potential target for PC, and its abnormal activation also indicates the progression of PC. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is the most common solid organ malignancy among men, outnumbering both lung and colorectal cancer, and it is the second leading cause of male tumor-related death in the United States due to high metastasis. Recently, leukemia inhibitory factor receptor (LIFR) has been found to play roles in multiple types of cancer. However, the roles of LIFR in the progression of PCa remain to be revealed. In this study, we found that LIFR plays an oncogenic role in PCa. The phosphorylation of LIFR at S1044 contributes to subsequent activation of the AKT pathway, inducing the expression of a series of proliferation and metastatic genes. Additionally, LIFR-S1044 is phosphorylated by ERK2 but not ERK1. The signal intensity of pLIFR-S1044 and pAKT S473 in PCa tissue displays a tight positive correlation. The ERK2/LIFR/AKT axis modulates PCa progression and offers a promising therapeutic and diagnostic target for PCa. [ABSTRACT FROM AUTHOR]

Objectives: The incidence of colorectal cancer (CRC) is increasing year by year and appears to be younger, due to the low early diagnosis rate and metastasis. It is difficult to remedy by conventional treatment. Here, we reported that tripartite motif containing protein 2 (TRIM2) could promote tumor growth, invasion and metastasis of CRC via a mechanism that involved EMT both in vitro and in vivo. Methods: First, we used immunohistochemistry to detect TRIM2 expression. Next, TCGA database was applied to the coorelation between TRIM2 and CRC progression. Then, the plasmids and lentivirus particles were used to manipulate TRIM2 expression in SW620 or HT29 cells. The assays of proliferation, adhesion, magration and invasion were employed to detect the migration and invasion ability of CRC cells. Finally, a tail injection of CRC cells was used to identify the role of TRIM2 in tumor metastasis. Results: TRIM2 expression was significantly higher in CRC tissues than in non-cancerous tissues and was significantly associated with some clinicopathological factors. Forced overexpression of TRIM2 promoted CRC cell proliferation, migration and invasion in vitro, while opposing results were observed when TRIM2 was depleted by short hairpin RNA. TRIM2 expression had reversely correlated with YAP signaling, which was a novel pathway way referred to tumorigenesis. Furthermore, animal metastasis models confirmed that the in vivo results were consistent with the outcomes in vitro. TRIM2 conducts its function during CRC cell metastasis by epithelial–mesenchymal transition (EMT). These results indicate that TRIM2 is a novel promoter of human colorectal cancer. [ABSTRACT FROM AUTHOR]

Apatinib, a novel tyrosine kinase inhibitor (TKI), has been confirmed for its efficacy and safety in the treatment of advanced gastric carcinoma and some other solid tumors. However, the direct functional mechanisms of tumor lethality mediated by apatinib have not yet been fully characterized, and the precise mechanisms of drug resistance are largely unknown. Here, in this study, we demonstrated that apatinib could induce both apoptosis and autophagy in human colorectal cancer (CRC) via a mechanism that involved endoplasmic reticulum (ER) stress. Moreover, activation of the IRE1α pathway from apatinib-induced ER stress is responsible for the induction of autophagy; however, blocking autophagy could enhance the apoptosis in apatinib-treated human CRC cell lines. Furthermore, the combination of apatinib with autophagy inhibitor chloroquine (CQ) tends to have the most significant anti-tumor effect of CRC both in vitro and in vivo. Overall, our data show that because apatinib treatment could induce ER stress-related apoptosis and protective autophagy in human CRC cell lines, targeting autophagy is a promising therapeutic strategy to relieve apatinib drug resistance in CRC. [ABSTRACT FROM AUTHOR]