αO-Conotoxin GeXIVA[1,2] Reduced Neuropathic Pain and Changed Gene Expression in Chronic Oxaliplatin-Induced Neuropathy Mice Model.

Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting painful neuropathy that occurs commonly during cancer management, which often leads to the discontinuation of medication. Previous studies suggest that the α9α10 nicotinic acetylcholine receptor (nAChR)-specific antagonist αO-conotoxin GeXIVA[1,2] is effective in CIPN models; however, the related mechanisms remain unclear. Here, we analyzed the preventive effect of GeXIVA[1,2] on neuropathic pain in the long-term oxaliplatin injection-induced CIPN model. At the end of treatment, lumbar (L4-L6) spinal cord was extracted, and RNA sequencing and bioinformatic analysis were performed to investigate the potential genes and pathways related to CIPN and GeXIVA[1,2]. GeXIVA[1,2] inhibited the development of mechanical allodynia induced by chronic oxaliplatin treatment. Repeated injections of GeXIVA[1,2] for 3 weeks had no effect on the mice's normal pain threshold or locomotor activity and anxiety-like behavior, as evaluated in the open field test (OFT) and elevated plus maze (EPM). Our RNA sequencing results identified 209 differentially expressed genes (DEGs) in the CIPN model, and simultaneously injecting GeXIVA[1,2] with oxaliplatin altered 53 of the identified DEGs. These reverted genes were significantly enriched in immune-related pathways represented by the cytokine-cytokine receptor interaction pathway. Our findings suggest that GeXIVA[1,2] could be a potential therapeutic compound for chronic oxaliplatin-induced CIPN management.

Corrigendum: Chloroquine Inhibits Stemness of Esophageal Squamous Cell Carcinoma Cells Through Targeting CXCR4-STAT3 Pathway.

[This corrects the article DOI: 10.3389/fonc.2020.00311.].

Cancer-associated fibroblasts induce monocytic myeloid-derived suppressor cell generation via IL-6/exosomal miR-21-activated STAT3 signaling to promote cisplatin resistance in esophageal squamous cell carcinoma.

Drug resistance remains the major obstacle limiting the effectiveness of chemotherapy for esophageal squamous cell carcinoma (ESCC)[1]. However, how stromal cells cooperate with immune cells to contribute to drug resistance is not yet fully understood. In this study, we observed that monocytic myeloid-derived suppressor cells (M-MDSCs) were correlated with cisplatin resistance in patients with ESCC. Furthermore, CAFs promoted differentiation of monocytes into M-MDSCs phenotypically and functionally in vitro. Mechanically, both interleukin (IL)-6 and exosome-packed microRNA-21 (miR-21) secreted by CAFs synergistically promoted the generation of M-MDSCs via activating the signal transducing activator of transcription 3 (STAT3) by IL-6 in an autocrine manner. Combined blocking of IL-6 receptor and inhibition of miR-21 significantly reversed CAF-mediated M-MDSC generation. Notably, the effects of CAFs on M-MDSC induction were abolished by inhibiting STAT3 signaling. Functionally, CAF-induced M-MDSCs promoted drug resistance of tumor cells upon cisplatin treatment. Clinically, ESCC patients with high infiltration of CAFs and CD11b+ myeloid cells had unfavorable predicted overall survival both in our cohort and in TCGA data. Taken together, our study reveals a paracrine and autocrine of IL-6 caused by CAFs co-activate STAT3 signaling, promoting the generation of M-MDSCs, and highlights the important role of CAFs in cooperation with M-MDSCs in promoting drug resistance, thus providing potential opportunities for reversing drug resistance through inhibition of STAT3 signaling.

α-Conotoxin TxID and [S9K]TxID, α3ß4 nAChR Antagonists, Attenuate Expression and Reinstatement of Nicotine-Induced Conditioned Place Preference in Mice.

Tobacco smoking has become a prominent health problem faced around the world. The α3ß4 nicotinic acetylcholine receptor (nAChR) is strongly associated with nicotine reward and withdrawal symptom. α-Conotoxin TxID, cloned from Conus textile, is a strong α3ß4 nAChR antagonist, which has weak inhibition activity of α6/α3ß4 nAChR. Meanwhile, its analogue [S9K]TxID only inhibits α3ß4 nAChR (IC50 = 6.9 nM), and has no inhibitory activity to other nAChRs. The present experiment investigates the effect of α3ß4 nAChR antagonists (TxID and [S9K]TxID) on the expression and reinstatement of nicotine-induced conditioned place preference (CPP) and explores the behaviors of acute nicotine in mice. The animal experimental results showed that TxID and [S9K] TxID could inhibit the expression and reinstatement of CPP, respectively. Moreover, both had no effect in acute nicotine experiment and the locomotor activity in mice. Therefore, these findings reveal that the α3ß4 nAChR may be a potential target for anti-nicotine addiction treatment. [S9K]TxID, α3ß4 nAChR antagonist, exhibit a superior effect for anti-nicotine addiction, which is promising to develop a novel smoking cessation drug.

Chloroquine Inhibits Stemness of Esophageal Squamous Cell Carcinoma Cells Through Targeting CXCR4-STAT3 Pathway.

Esophageal squamous cell carcinoma (ESCC) is one of the most prevalent cancers worldwide. Recent studies have shown that cancer stem cells (CSCs) are present in ESCC, are thought to lead to aggressive tumor behavior and the prognosis. The CXC chemokine receptor 4 (CXCR4), is regarded as a putative CSCs marker in various malignancies. Here, we demonstrate that CXCR4 played a key role in ESCC progression and CXCR4 positive ESCC cells possessed stem-like properties. Furthermore, the anti-malarial agent chloroquine (CQ) targeted CXCR4-positive ESCC cells via STAT3 pathway. Therefore, CQ with anti-CSCs effects may be an effective adjunct to current ESCC chemotherapy regimens.

Correction: Gene function analysis and underlying mechanism of esophagus cancer based on microarray gene expression profiling.

[This corrects the article DOI: 10.18632/oncotarget.22160.].

Large-scale analysis reveals the specific clinical and immune features of B7-H3 in glioma.

Background: B7-H3 is an immune checkpoint member that belongs to B7-CD28 families and plays a vital role in the inhibition of T-cell function. Importantly, B7-H3 is widely overexpressed on solid tumors, making it become an attractive target for cancer immunotherapy. To clarify the expression panel of B7-H3 in glioma, we explored the clinical and immune features of B7-H3 expression in a large-scale study. Methods and patients: Totally, 1323 glioma samples from Chinese Glioma Genome Atlas (CGGA) dataset, including 325 RNAseq data and 301 mRNA microarray data, and The Cancer Genome Atlas (TCGA) dataset, including 697 RNAseq data, were gathered into our research. The statistical analysis and graphical work were mainly realized by R language. Results: B7-H3 expression was found positively correlated with the grade of malignancy, which might be caused by hypomethylation. The expression level of B7-H3 was consistently up-regulated in IDH wild-type glioma and highly enriched in mesenchymal subtype. GSEA analysis suggested that B7-H3 related genes were more involved in immune response and angiogenesis in glioma. Moreover, B7-H3 showed a consistent positive relationship with stromal and immune cell populations. Further analysis confirmed that B7-H3 played an important role in T-cell-mediated immunity, especially in T-cell-mediated immune response to tumor cell. Circos plots revealed that B7-H3 was tightly associated with most B7 members and other immune checkpoints. Univariate and multivariate cox analysis demonstrated that B7-H3 was an independent prognosticator for glioma patients. Conclusion: B7-H3 represents the malignant phenotype of glioma and independently predicted worse prognosis in glioma patients. Moreover, B7-H3 collaborating with other checkpoint members may contribute to the dysfunctional phenotype of T cell. These findings will be helpful for further optimizing immunotherapies for glioma.

Regulatory T cells were recruited by CCL3 to promote cryo-injured muscle repair.

Skeletal muscle injury is a common symptom in daily life. After injury, a distinct population of regulatory T cells (Tregs) will infiltrate skeletal muscle in acute and chronic injury sites. However, the mechanism by which Tregs rapidly accumulate to the site of acute injury remains unclear. BALB/c mice were used to establish a cryo-injured model. Percentage of Tregs in the normal and cryo-injured tissues was detected on different days by flow cytometry. Then, the major factors that contribute to the repair of skeletal muscle by Tregs and the chemokines associated with the chemotaxis of Tregs in the paired muscle were analyzed by qRT-PCR. Finally, Tregs were sorted out by magnetic beads and the transwell analysis was performed in vitro. Compared to the normal muscle, the proportion of Tregs was dramatically-increased in the cryo-injured muscle on day 4. These Tregs produced high level of repair related factors such as amphiregulin (Areg), IL-10 and TGF-ß in the cryo-injured muscle. In addition, we found that CCL3, CCL4, CCL5 were the main chemokines that highly expressed in the injured skeletal muscle compared to the normal skeletal muscle. Simultaneously, their receptors CCR1 and CCR5 were highly expressed on Tregs in cryo-injured muscle compared with the normal muscle. Transwell analysis showed CCL3 can significantly chemotize Tregs and the antibody of CCR1 could reverse the chemotaxis in vitro. These results suggest that Tregs in the cryo-injured muscle play a pivotal role that can promote the regeneration of skeletal muscle and CCL3 may serve as the key chemokine to recruit Tregs to the injury sites.

Role of CXCR7 as a Common Predictor for Prognosis in Solid Tumors: a Meta-Analysis.

Background: Accumulating evidence indicated that the CXC chemokine receptor (CXCR) 7 (CXCR7) was overexpressed in a variety of tumors. However, the value of the CXCR7 expression in predicting prognosis in solid tumors remains controversial. Therefore, we performed this meta-analysis to evaluate the correlation between CXCR7 expression and lymph node metastasis (LNM), tumor pathological grade and survival, including overall survival (OS), disease-free survival (DFS) and recurrence-free survival (RFS). Methods: Eligible studies were searched in PubMed, Web of Science, and PMC up to April 2018. A total of 27 studies were included in this meta-analysis. Odds ratio (OR), hazard ratio (HR) and 95 % confidence intervals (CI) were used as effect measures. Results: The meta-analysis showed that high expression of CXCR7 predicted a high risk of LNM (pooled OR = 2.22, 95%CI: 1.41-3.50), high tumor grade (pooled OR = 1.94, 95%CI: 1.20-3.13), poor OS (pooled HR = 1.66, 95%CI: 1.30-2.03), and poor DFS/RFS (pooled HR = 1.82, 95%CI: 1.21-2.43). Subgroup analysis showed that CXCR7 expression had a positive correlation with LNM in pan-adenocarcinoma subgroup (pooled OR = 3.73, 95%CI: 2.21-6.30), while no correlation was found in pan-squamous cancer subgroup (pooled OR = 1.29, 95%CI: 0.56-2.96). Subgroup analysis of tumor grade revealed that high expression of CXCR7 predicted high tumor grade both in pan-squamous cancer and pan-adenocarcinoma (pooled OR = 3.58, 95%CI: 1.39-9.22, pooled OR = 2.25, 95%CI: 1.20-4.20). As in OS group, we divided the data based on analysis method and it turned out that overexpressed CXCR7 predicted worse OS both in multivariate analysis (pooled HR =1.57, 95%CI: 1.12-2.01) and univariate analysis subgroup (pooled HR =1.86, 95%CI: 1.23-2.49). Conclusions: Our meta-analysis revealed that high expression of CXCR7 predicted unfavorable prognosis and may serve as potential targets of cancer therapy.

Efficacy of Early Enteral Immunonutrition on Immune Function and Clinical Outcome for Postoperative Patients With Gastrointestinal Cancer.

BACKGROUND: Nutrition support is crucial for patients with gastrointestinal (GI) cancer after the operation. However, the controversy over the application of parenteral nutrition (PN) and early enteral immunonutrition (EEIN) has no determinate conclusion. MATERIALS AND METHODS: We compared the effects of PN and EEIN on the postoperative nutrition condition, immune status, inflammation level, long-term survival, and quality of life of the patients with GI cancer. Seventy-eight patients were randomly divided into the PN group (n = 44) or EEIN group (n = 34). After an 8-day nutrition treatment, clinical and immunological parameters were evaluated. RESULTS: The EEIN group had a significantly shorter hospital stay and higher body mass index level on postoperative day 30 than those in the PN group (P < .05). However, total hospital cost and incidences of short-term postoperative complications had no significant difference (P > .05). The percentages of CD4+ , natural killer, and natural killer T lymphocyte cells and the ratio of CD4+ /CD8+ in peripheral blood were significantly increased. Compared with the PN group, the EEIN group had a higher expression of activated cell surface markers such as CD27 and CD28. In addition, the secretion of interleukin (IL)-2 and interferon-γ was significantly higher, and the secretion of tumor necrosis factor-α and IL-10 was lower. Complication-free survival in the EEIN group were longer than those in the PN group (P = .04). CONCLUSION: EEIN is superior to PN in improving nutrition status, enhancing immune function, and elevating quality of life.

Gene function analysis and underlying mechanism of esophagus cancer based on microarray gene expression profiling.

Esophageal cancer (EC) is one of the most common digestive malignant tumors worldwide. Over the past decades, there have been minimal improvements in outcomes for patients with EC. New targets and novel therapies are needed to improve outcomes for these patients. This study aimed to explore the molecular mechanisms of EC by integrated bioinformatic analyses of the feature genes associated with EC and correlative gene functions which can distinguish cancerous tissues from non-cancerous tissues. Gene expression profile GSE20347 was downloaded from Gene Expression Omnibus (GEO) database, including 17 EC samples and their paired adjacent non-cancerous samples. The differentially expressed genes (DEGs) between EC and normal specimens were identified and then applied to analyze the GO enrichment on gene functions and KEGG pathways. Corresponding Pathway Relation Network (Pathway-net) and Gene Signal Network (signal-net) of DEGs were established based on the data collected from GCBI datasets. The results showed that DEGs mainly participated in the process of cell adhesion, cell proliferation, survival, invasion, metastasis and angiogenesis. Aberrant expression of PTK2, MAPK signaling pathway, PI3K-Akt signaling pathway, p53 signaling pathway and MET were closely associated with EC carcinogenesis. Importantly, Interleukin 8 (IL8) and C-X-C chemokine receptor type 7 (CXCR-7) were predicted to be significantly related to EC. These findings were further validated by analyzing both TCGA database and our clinical samples of EC. Our discovery provides a registry of genes and pathways that are disrupted in EC, which has the potential to be used in clinic for diagnosis and target therapy of EC in future.

Long noncoding RNA MALAT1 promotes malignant development of esophageal squamous cell carcinoma by targeting ß-catenin via Ezh2.

Evidences have shown that lncRNAs involve in the initiation and progression of various cancers including esophageal squamous cell carcinoma (ESCC). The aberrant expression of lncRNA MALAT1 was investigated in 106 paired ESCC tissues and adjacent non-cancerous tissues by qRT-PCR. Down-regulated MALAT1 and Ezh2 over-expression plasmid were constructed respectively to analyze the expression of ß-catenin, Lin28 and Ezh2 genes. We found that the MALAT1 expression level was higher in human ESCC tissues (P=0.0011), which was closely correlated with WHO grade (P=0.0395, P=0.0331), lymph node metastasis (P=0.0213) and prognosis (P=0.0294). Silencing of MALAT1 expression inhibited cell proliferation, migration and tumor sphere formation, while increasing cell apoptosis of esophageal cancer in vitro. Down-regulation of MALAT1 decreased the expression of ß-catenin, Lin28 and Ezh2 genes, while over-expressed Ezh2 combined with MALAT1 down-regulation completely reversed the si-MALAT1-mediated repression of ß-catenin and Lin28 in esophageal cancer cells. Animal experiments showed that knockdown of MALAT1 decreased tumor formation and improved survival. MALAT1 promotes the initiation and progression of ESCC, suggesting that inhibition of MALAT1 might be a potential target for treatment of ESCC.