Cancer is currently one of the leading causes of death worldwide and is one of the most challenging major public health problems. The main challenges faced by clinicians in the management and treatment of cancer mainly arise from difficulties in early diagnosis and the emergence of tumor chemoresistance and metastasis. The structures of chemokine receptor 9 (CCR9) and its specific ligand chemokine ligand 25 (CCL25) have been elucidated, and, interestingly, a number of studies have demonstrated that CCR9 is a potential tumor biomarker in diagnosis and therapy, as it has been found to be highly expressed in a wide range of cancers. This expression pattern suggests that CCR9 may participate in many important biological activities involved in cancer progression. Researchers have shown that CCR9 that has been activated by its specific ligand CCL25 can interact with many signaling pathways, especially those involved in tumor chemoresistance and metastasis. This review, therefore, focuses on CCR9 induction activity and summarizes what is currently known regarding its role in cancers and its potential application in tumor-targeted therapy.

Paternally expressed gene 10 (PEG10) has been identified as a genetic imprinted gene, which is important for apoptosis resistance in cancer cells. Mounting evidence suggests that PEG10 is expressed in the majority of hepatocellular carcinoma (HCC) cells with growth-promoting activity. In the present study, we evaluated the correlation between PEG10 expression and the clinicopathological features of lung, breast and HCC tumors, and predicted the relationship between survival and expression levels of PEG10 in lung cancer patients. Furthermore, we chose non-small cell lung cancer cell line A549 as a model to analyze the function of PEG10 in proliferation and metastasis in vitro. Our results revealed that expression of PEG10 was closely correlated with clinical TNM grade and patient prognosis in lung cancer. PEG10 enhanced cell proliferation and promoted tumor cell migration and invasion by upregulating the expression of β-catenin, MMP-2 and MMP-9, and decreased the expression of E-cadherin in the A549 cells. Our findings provide significant insight into the molecular mechanisms of lung cancer and offer novel ideas for designing new therapeutic targets for lung carcinoma.

BackgroundGlucose-6-phosphate isomerase (GPI) plays an important role in glycolysis and gluconeogenesis. However, the role of GPI in lung adenocarcinoma (LUAD) remains unclear.MethodsAll original data were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and integrated via R 3.2.2. GPI expression was explored with TCGA, GEO, and Oncomine databases. Immunohistochemistry staining was used to analyze GPI expression in clinical specimens. The correlations between GPI and cancer immune characteristics were analyzed via the TIMER and TISIDB databases. GPI-specific siRNAs were used to verify the role of GPI expression on cell proliferation and cell cycle distribution.ResultsIn general, GPI is predominantly overexpressed and has reference value in the diagnosis and prognostic estimation of LUAD. Upregulated GPI was associated with poorer overall survival, clinical stage, N stage, and primary therapy outcome in LUAD. Mechanistically, we identified a hub gene that included a total of 56 GPI-related genes, which were tightly associated with the cell cycle pathway in LUAD patients. Knockdown of GPI induced cell proliferation inhibition and cell cycle arrest. GPI expression was positively correlated with infiltrating levels of Th2 cells and regulatory T cells (Tregs); in contrast, GPI expression was negatively correlated with infiltrating levels of CD8+ T cells, central memory T cells, dendritic cells, macrophages, mast cells, and eosinophils. GPI was negatively correlated with the expression of immunostimulators, such as CD40L, IL6R, and TMEM173, in LUAD.ConclusionGPI may play an important role in the cell cycle and can be used as a prognostic biomarker for determining the prognosis and immune infiltration in LUAD.

Radiotherapy has played a limited role for the treatment of human esophageal cancer owing to the risk of tumor radioresistance. Core 1 β1, 3-galactosyltransferase (C1GalT1), which catalyzes the formation of core 1 O-glycan structures, is frequently overexpressed during tumorigenesis. However, the exact effects and mechanisms of C1GalT1 in the radioresistance of esophageal cancer remain unclear. In this study, Public databases and our data revealed that C1GalT1 expression was up-regulated in esophageal cancer tissues and was associated with poor survival. Upon irradiation, we found that esophageal cancer cells with high levels of C1GalT1 could tolerate cell death and had increased resistance to radiotherapy. Irradiation also promoted the expression of C1GalT1 and core 1 O-glycan structures. C1GalT1 knockdown increased the radiosensitivity of esophageal cancer cells, and attenuated irradiation-enhanced migration and invasion. Mechanistic investigations showed that C1GalT1 modified O-glycan structures on β1-integrin and regulated its downstream focal adhesion kinase (FAK) signaling. Furthermore, β1-integrin-blocking antibody and FAK inhibitor enhanced radiation-induced apoptosis in esophageal cancer cells. Together, our results indicate that C1GalT1 is a major determinant of radioresistance via modulation of β1-integrin glycosylation. C1GalT1 may be a potent molecular target for enhancing the efficacy of radiotherapy.

Cisplatin resistance is one of the main causes of chemotherapy failure and tumor progression in non-small cell lung cancer (NSCLC). Emodin has been demonstrated to induce NSCLC cell apoptosis and act as a potential cancer therapeutic agent. However, whether emodin could affect NSCLC cell sensitivity toward cisplatin remains unclear. The present study aimed to determine the effect of emodin and cisplatin combination on the chemosensitivity of NSCLC cells. A549 and H460 cells were treated with different concentrations of cisplatin and/or emodin. Cell Counting Kit-8, fluorescence microscopy, immunofluorescence assays and flow cytometry were used to determine cell proliferation, drug efflux, DNA damage level and cell apoptosis, respectively. P-glycoprotein (Pgp) and multidrug resistance-associated protein 1 (MRP1) expression was detected by western blotting. The results demonstrated that emodin and cisplatin inhibited the proliferation of A549 and H460 cells. Furthermore, emodin inhibited the drug efflux in A549 and H460 cells in a dose-dependent manner. In addition, emodin enhanced cisplatin-induced apoptosis and DNA damage in A549 and H460 cells. Emodin also decreased Pgp expression in A549 and H460 cells in a dose-dependent manner; however, it had no effect on MRP1 expression. Taken together, the results from the present study demonstrated that emodin can increase A549 and H460 cell sensitivity to cisplatin by inhibiting Pgp expression. Emodin may therefore be considered as an effective adjuvant for cisplatin treatment.

Cumulative evidence suggests that long non-coding RNAs (lncRNAs) may be good biomarkers in various types of tumors. In the present study, we mined lncRNA expression profiling in 739 lung cancer patients from Gene Expression Omnibus (GEO) datasets. A risk score model was constructed based on the expression data of these eight lncRNAs in the training dataset (GSE30219). The validation for the association was performed in three independent testing sets (GSE31210, GSE37745 and GSE19188). Finally, a set of eight lncRNA genes (AK021595, BC030759, AK000053, AK124307, BC020384, AK022024, CR615992 and AF085995) were identified by the random survival forest algorithm. Using a risk score based on the expression signature of these lncRNAs, we separated the patients into low-risk and high-risk groups with significantly different survival times in the training set. This finding was validated in the other three testing sets. Further study revealed that the eight-lncRNA expression signature was independent of age and gender. Gene Set Enrichment Analysis (GSEA) suggested that lncRNAs were involved in cell cycle and DNA replication signaling pathways. Therefore, the eight lncRNAs may be candidate prognostic biomarkers for lung cancer patients.

Adult T-cell acute lymphoblastic leukemia (T-ALL) is a refractory leukemia. We previously showed that CCL25/CCR9 promotes T-ALL metastasis. In the present study, we assessed the effects of CCL25 on Wnt expression and the effects of Wnt5a and CCL25 on PI3K/Akt and RhoA activation. Transwell assays and mouse xenograft experiments were utilized to assess the effects of Wnt5a and CCL25 on MOLT4 cell invasion, migration and metastasis. The effects of Wnt5a on MOLT4 cell actin polarization and pseudopodium formation were examined using laser scanning confocal microscopy and scanning electron microscopy. CCL25 induced Wnt5a expression in MOLT4 cells by promoting protein kinase C (PKC) expression and activation. Wnt5a promoted MOLT4 cell migration, invasion, actin polarization, and lamellipodium and filopodia formation via PI3K/Akt-RhoA pathway activation. These effects were rescued by PI3K/Akt or RhoA knockdown or inhibition. Additionally, Wnt5a in cooperation with CCL25 promoted MOLT4 cell mouse liver metastasis and stimulated RhoA activation. These results show that CCL25/CCR9 upregulates Wnt5a by promoting PKC expression and activation in MOLT4 cells. This in turn promotes cell migration and invasion via PI3K/Akt-RhoA signaling, enhancing cell polarization and pseudopodium formation. These findings indicate that the PI3K/Akt-RhoA pathway is likely responsible for Wnt5a-induced adult T-ALL cell migration and invasion.

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