Principles and current clinical landscape of NK cell engaging bispecific antibody against cancer.

Monoclonal antibody-based targeted therapies have greatly improved treatment options for patients by binding to the innate immune system. However, the long-term efficacy of such antibodies is limited by mechanisms of drug resistance. Over the last 50 years, with advances in protein engineering technology, more and more bispecific antibody (bsAb) platforms have been engineered to meet diverse clinical needs. Bispecific NK cell engagers (BiKEs) or tri-specific NK cell engagers (TriKEs) allow for direct targeting of immune cells to tumors, and therefore resistance and serious adverse effects are greatly reduced. Many preclinical and clinical trials are currently underway, depicting the promise of antibody-based natural killer cell engager therapeutics. In this review, we compile worldwide efforts to explore the involvement of NK cells in bispecific antibodies. With a particular emphasis on lessons learned, we focus on preclinical and clinical studies in malignancies and discuss the reasons for the limited success of NK-cell engagers against solid tumors, offering plausible new ideas for curing some advanced cancers shortly.

CCL3-CCR5 axis promotes cell migration and invasion of colon adenocarcinoma via Akt signaling pathway.

BACKGROUND: Infiltration of tumor-associated macrophages (TAMs) can promote tumorigenesis and development. C-C motif chemokine ligand 3 (CCL3) was reported to be derived from TAMs and tumor cells and facilitate the progression of several cancers. Nevertheless, whether CCL3 can be derived from TAMs and tumor cells of colon adenocarcinoma (COAD) is unclarified. METHODS: Peripheral blood monocytes-derived macrophages were polarized by the conditioned medium from COAD cells to establish TAM-like macrophages (TAM1/2). RT-qPCR and western blotting were used for detection of expression levels of CCL3 and its receptors C-C motif chemokine receptor 1 (CCR1) and CCR5 in TAM1/2 and COAD cells. Immunofluorescence staining was utilized for evaluating CCL3, CD163 and CCR5 expression. The Akt signaling pathway-associated protein levels were measured by western blotting. Transwell assays were used for assessing cell migration and invasiveness. RESULTS: CCL3 displayed a high level in TAMs and cancer cells of COAD. CCL3 activated the Akt signaling pathway by binding to CCR5. CCL3-CCR5 axis facilitated COAD cell migration and invasiveness by activating the Akt signaling. CCL3 derived from both TAMs and cancer cells contributed to the malignant behaviors of COAD cells. High expression of CCL3/CCR5 was closely associated with poor prognoses of COAD patients. CONCLUSION: CCL3-CCR5 interaction promotes cell migration and invasiveness, and functions as a prognostic biomarker for COAD.

The efficacy and safety of traditional Chinese medicine physiotherapy combined with acupoint injection on diabetic peripheral neuropathy: A protocol for systematic review and meta-analysis.

BACKGROUND: The efficacy and safety of traditional Chinese medicine physiotherapy combined with acupoint injection in treating diabetic peripheral neuropathy remains unknown. As a result, we will conduct a systematic review and meta-analysis to assess the evidence. METHODS: We will look for pertinent randomized controlled trials in the following databases: China National Knowledge Infrastructure, WanFangData, Chinese biological medical database, Medline, Cochrane Library, PubMed, and Embase up to January 2022. Following the standards of Cochrane Review 6.2, 2 researchers independently evaluated the quality of the evidence in the relevant papers. Data analysis will be conducted by using Review Manager 5.4, including statistical analysis, subgroup analysis, making forest plot and funnel chart. RESULTS: The results will be submitted to a peer-reviewed journal. CONCLUSION: The research will verify the safety and efficacy of traditional Chinese medicine physiotherapy in combination with acupoint injection for diabetic peripheral neuropathy.

The efficacy and safety of catheter balloon dilatation in the treatment of dysphagia after stroke: A protocol for systematic review and meta-analysis.

BACKGROUND: Dysphagia is a serious complication after stroke, which has a significant influence on the health as well as life quality of global people. Patients with dysphagia tend to be a higher risk rate of an aspiration than general person. Catheter balloon dilatation is an additional therapy for treating dysphagia in recent years, which can improve the symptom of achalasia of cricopharyngeal muscle. This research will be used for confirming the efficacy and safety of the catheter balloon dilatation for resolving dysphagia. METHODS: We intend to search literature related to the research in different databases, for instance, China National Knowledge Infrastructure, Wanfang Data, PubMed, Cochrane Library, and Embase up to January 2022. Literature selection, data collection, as well as assessment of bias risk, will be carried out by 2 independent researchers. Data analysis will be conducted by using Stata and review manager 5.4. RESULTS: The results will be submitted to a peer-reviewed journal. CONCLUSION: The research will verify whether or not catheter balloon dilatation can improve dysphagia by submitting high-quality data syntheses. REGISTRATION NUMBER: CRD42022358433.

Long noncoding RNA CA3-AS1 suppresses gastric cancer migration and invasion by sponging miR-93-5p and targeting BTG3.

The long noncoding RNAs (lncRNAs) are a class of noncoding RNAs that are broadly expressed in various biological cells and function in regulating gene expression. However, the function of lncRNAs and the role of lncRNAs in gastric cancer remain to be determined. Herein, the function of lncRNA CA3-AS1 was investigated in gastric cancer. Firstly, we found that the expression level of CA3-AS1 was decreased in gastric cancer cell lines and tissues. Then, CA3-AS1 overexpression inhibited the gastric cancer cells migration and invasion and knockdown of CA3-AS1 enhanced the gastric cancer cells migration and invasion. Moreover, FISH assays and qPCR results revealed that CA3-AS1 was mainly expressed in the cytoplasm of gastric cancer cells. Then, the relationship between CA3-AS1 and miR-93-5p was explored. Luciferase reporter assays results showed that miR-93-5p was a direct target of CA3-AS1 in SGC-7901 and BCG-823. Furthermore, BTG3 was identified as a direct target gene of miR-93-5p. Restore experiments showed that CA3-AS1 upregulated the expression level of BTG3 and inhibited the gastric cancer cells invasion by sponging miR-93-5p. Finally, we found that CA3-AS1 inhibited the metastasis ability of gastric cancer cells in vivo. Above results suggested that CA3-AS1 acted as anti-oncogene in gastric cancer and might become a vital target for clinical treatment.

RNA-binding protein RBM38 inhibits colorectal cancer progression by partly and competitively binding to PTEN 3'UTR with miR-92a-3p.

RNA-binding motif protein 38 (RBM38) belongs to the RNA recognition motif family of RNA-binding proteins (RBPs). RBM38 was previously identified to suppress tumorigenesis in colorectal cancer (CRC). RBM38 was also reported to bind to the 3'UTR of phosphatase and tensin homolog gene on chromosome 10 (PTEN), a tumor suppressor involved in many cellular processes, to stabilize PTEN transcripts. In the present study, we investigated the mechanisms underlying the regulation of RBM38 in CRC. Reverse transcription quantitative polymerase chain reaction and western blotting detected the expression of RBM38, PTEN, and miR-92a-3p. Colony formation, EdU, sphere formation, Transwell invasion, and in vivo assays examined the influence of RBM38 on CRC progression. Furthermore, RNA immunoprecipitation (RIP) assay determined the binding site of RBM38 on PTEN 3'UTR. The binding of miR-92a-3p or RBM38 on PTEN 3'UTR was assessed by luciferase reporter and RIP assays. We discovered that RBM38 was downregulated in CRC cells and tissues. RBM38 repressed CRC progression in vitro and in vivo. Furthermore, RBM38 upregulated and stabilized PTEN expression. Interestingly, the overexpression of PTEN reversely attenuated the promotion of RBM38 depletion on CRC progression. Additionally, RBM38 competed with miR-92a-3p in binding to PTEN 3'UTR. In conclusion, RBM38 inhibits CRC progression by competitively binding to PTEN 3'UTR with miR-92a-3p.

LncRNA NCK1-AS1 exerts oncogenic property in gastric cancer by targeting the miR-22-3p/BCL9 axis to activate the Wnt/ß-catenin signaling.

Long noncoding RNAs (lncRNAs) exert crucial effects on the development of many malignancies, including gastric cancer. Herein, we investigated the role of lncRNA noncatalytic region of tyrosine kinase adaptor protein 1 (NCK1) divergent transcript (NCK1-DT, also known as NCK1-AS1) in gastric cancer. Reverse transcription quantitative polymerase chain reaction demonstrated that NCK1-AS1 exhibited high expression in gastric cancer tissues and cells. In vitro assays including MTT, colony formation, Transwell, wound healing and sphere formation assays indicated that NCK1-AS1 depletion inhibited cell proliferation, migration, invasion and stemness maintenance. Luciferase reporter and RIP assays suggested that NCK1-AS1 functioned as a competitive endogenous RNA (ceRNA) for miR-22-3p to positively modulate BCL9 expression. BCL9 was a target gene of miR-22-3p. According to western blot analysis and TOP/FOP flash assay, NCK1-AS1 activated the Wnt/ß-catenin signaling via the miR-22-3p/BCL9 axis. Furthermore, rescue experiments verified that NCK1-AS1 affected cellular processes by activating the Wnt/ß-catenin signaling pathway via the miR-22-3p/BCL9 axis. Tumor xenograft model validated that NCK1-AS1 promoted tumor growth in vivo via the Wnt/ß-catenin signaling by upregulating BCL9 expression. Overall, NCK1-AS1 functions as an oncogene and promotes gastric cancer progression via the miR-22-3p/BCL9-Wnt/ß-catenin signaling pathway.

Circ_0110805 Knockdown Enhances Cisplatin Sensitivity and Inhibits Gastric Cancer Progression by miR-299-3p/ENDOPDI Axis.

BACKGROUND: Gastric cancer is a prevalent primary stomach tumor. Cisplatin is frequently used to treat gastric cancer. However, the resistance of cisplatin in gastric cancer often occurs, which brings a heavy burden to gastric cancer treatment. METHODS: In this study, we revealed a novel underlying mechanism about cisplatin-resistant effect in gastric cancer. A Cell Counting Kit-8 (CCK-8) cell viability assay and a xenograft model were performed to evaluate the function of circRNA in the cisplatin resistance of gastric cancer. RESULTS: Compared with control groups, we observed that circ_0110805 was highly expressed, the mRNA and protein expression levels of ENDOPDI were dramatically upregulated, and the expression of miR-299-3p was significantly downregulated in gastric cancer cells, cisplatin-resistant gastric cancer tissues or cells. Functionally, circ_0110805 knockdown improved cisplatin sensitivity, induced cell apoptosis, whereas repressed cell viability, migration and invasion in AGS/DDP and HGC-27/DDP cells, which was reversed by miR-299-3p inhibitor. Additionally, ENDOPDI overexpression hindered the effects of miR-299-3p on cisplatin sensitivity and gastric cancer progression. Circ_0110805 knockdown enhanced cisplatin sensitivity in vivo. Mechanistically, circ_0110805 acted as a sponge of miR-299-3p and its targeted ENDOPDI. CONCLUSION: We showed that circ_0110805 knockdown increased the sensitivity of gastric cancer to cisplatin, which also repressed gastric cancer progression by sponging miR-299-3p to downregulate ENDOPDI expression. It might provide a new insight for future studying cisplatin-resistant gastric cancer.

The landscape of DNA methylation in hepatocellular carcinoma.

Better understanding of the relationship between changes in the overall methylation status of hepatocellular carcinoma (HCC) and disease progression will help us find good strategies for the early detection and treatment of HCC patients. The purpose of the study was to study the relations between the methylation status changes in HCC patients and progression of the disease to enable early detection and treatment of HCC patients. First, the DNA methylation data of 50 HCC samples and the surrounding normal samples were extracted and the change pattern of methylation status in the DNA promoter region of HCC samples against that of normal samples was studied. Then, some DNA methylation genes that could accurately identify cancer and cancer-adjacent tissues were identified using the k-top scoring pair method. Also, a prognostic signature that could predict the survival of HCC patients was constructed based on the overall survival time and death information of the early HCC patients. Finally, the obtained prognostic signature was verified. In conclusion, this study described the changes in the methylation spectrum during the development of HCC and identified genes associated with HCC progression and prognosis, which may offer new opportunities for the diagnosis and treatment of HCC.

Endoplasmic reticulum resident oxidase ERO1-Lalpha promotes hepatocellular carcinoma metastasis and angiogenesis through the S1PR1/STAT3/VEGF-A pathway.

Mounting evidence demonstrates that expression of ERO1α, an endoplasmic reticulum (ER)-resident oxidase, is a poor prognosis factor in a variety of human cancers. However, the clinical relevance of ERO1α and its molecular mechanisms underlying tumor progression have not been determined for hepatocellular carcinoma (HCC). ERO1α expression levels in HCC tissues and cells were detected by quantitative real-time PCR and western blotting. ERO1α shRNAs and overexpression vector were transfected into HCC cells to downregulate or upregulate ERO1α expression. In vitro and in vivo assays were performed to investigate the function of ERO1α in invasion, metastasis, and angiogenesis of HCC. We found high ERO1α expression in HCC tissues and cells that was significantly associated with metastasis and poor clinicopathologic features of vascular invasion, advanced Edmondson Grade, and TNM stage. Loss-of-function and gain-of-function studies showed that ERO1α prompted migration, invasion, epithelial-mesenchymal transition (EMT), and angiogenesis of HCC cells both in vitro and in vivo. Further studies verified a positive correlation between ERO1α and S1PR1, upregulated in metastatic HCC tissues compared with HCC tissues without metastasis. S1PR1 knockdown markedly diminished the effects of ERO1α on HCC cell migration, invasion and vascular endothelial growth factor (VEGF) expression. Most importantly, ERO1α knockdown significantly repressed the death of HCC xenograft mouse models by reducing tumor distant metastasis, and host angiogenesis by suppressing the expression of S1PR1, p-STAT3, and VEGF-A in HCC cells. Our findings suggest that ERO1α is significantly correlated with reduced survival and poor prognosis, and promotes HCC metastasis and angiogenesis by triggering the S1PR1/STAT3/VEGF-A signaling pathway. ERO1α might be a novel candidate in HCC prognosis and therapy.

KIT performed as a driver gene candidate affecting the survival status of patients with stomach adenocarcinoma.

Stomach adenocarcinoma is estimated to cause 10,000 deaths in the US in 2016 and is the third most deadly cancer in China. We aim to identify the proteins and the genes that have impact on the prognosis of patients with stomach adenocarcinoma. Data of patients with stomach adenocarcinoma were retrieved from The Cancer Genome Atlas (TCGA). Proteins whose expression levels were highly correlated with survival status of patients were figured out. The expression levels of their mRNAs and their roles in the pathway were used to determine the driver gene candidates. The effects of mutations on the genes encoding KIT on mRNA expressions were carried. Ten antibodies were figured out to have significant correlation with stomach cancer prognosis. The coefficients of COXPH models matches their roles in the previous studies. The expression levels of mRNAs versus proteins suggested that KIT might act as a driver gene, which was also the central in the pathway of other selected proteins. The missense mutations on the gene encoding KIT led to the low expression of its mRNAs and there were much fewer nonsense mutations compared with other genes. It suggested that the important role of KIT as an oncogene in the progression of cancer, as well as a tyrosine-protein kinase during the normal activity. Ten antibodies, corresponding to fifteen proteins, were highly correlated with patients' survival time, within which KIT played a critical roles. It suggested that KIT might be used as biomarker or as target of cancer therapies.