A Biodegradable Nano-Drug Delivery Platform for Co-Delivery of Minocycline and Chitosan to Achieve Efficient and Safe Non-Surgical Periodontitis Therapy.

INTRODUCTION: Mesoporous silica nanoparticles (MSN) are widely used as ideal nanovehicles for the delivery of chemotherapeutic drugs. However, the balance between high anti-periodontitis activity and low biotoxicity has been challenging to maintain in most relevant studies owing to the slow degradation of silica in living organisms. METHOD: In this study, -responsive hydroxyapatite (HAP) was doped into the MSN skeleton, and the chemotherapeutic drug minocycline hydrochloride (MH) was loaded into the pores of MSN, forming a negatively charged drug delivery system. Cationic chitosan (COS) is a biodegradable material with high antibacterial performance and good biosafety. In this study, COS was immobilized on the surface of the drug-loaded particles through stable charge interaction to construct a composite drug delivery system (MH@MSNion@COS). RESULTS: In vitro and cellular experiments demonstrated effective degradation of the nanocarrier system and synchronized controlled release of the drug. Notably, compared with single MH administration, this system, in which MH and COS jointly regulated the expression levels of periodontitis- associated inflammatory factors (TNF-α, IL-6, IL-1ß, and iNOS), better inhibited the progress of periodontitis and induced tissue regeneration without showing significant toxic side effects in cells. CONCLUSION: This system provides a promising strategy for the design of intelligent, efficient, and safe anti-periodontitis drug delivery systems.

A Carbon-Caged Rhodamine Generating Nitrosoperoxycarbonate for Photoimmunotherapy.

Photoimmunotherapy is a promising cancer treatment modality. While potent 1-e- oxidative species are known to induce immunogenic cell death (ICD), they are also associated with unspecific oxidation and collateral tissue damage. This difficulty may be addressed by post-generation radical reinforcement. Namely, non-oxidative radicals are first generated and subsequently activated into powerful oxidative radicals to induce ICD. Here, we developed a photo-triggered molecular donor (NPCD565) of nitrosoperoxycarbonate (ONOOCO2-), the first of its class to our knowledge, and further evaluated its feasibility for immunotherapy. Upon irradiation of NPCD565 by light within a broad spectral region from ultraviolet to red, ONOOCO2- is released along with a bright rhodamine dye (RD565), whose fluorescence is a reliable and convenient build-in reporter for the localization, kinetics, and dose of ONOOCO2- generation. Upon photolysis of NPCD565 in 4T1 cells, damage-associated molecular patterns (DAMPs) indicative of ICD were observed and confirmed to exhibit immunogenicity by induced maturation of dendritic cells. In vivo studies with a bilateral tumor-bearing mouse model showcased the potent tumor-killing capability of NPCD565 of the primary tumors and growth suppression of the distant tumors. This work unveils the potent immunogenicity of ONOOCO2-, and its donor (NPCD565) has broad potential for photo-immunotherapy of cancer.

CASC19: An Oncogenic Long Non-coding RNA in Different Cancers.

A 324 bp lncRNA called CASC19 is found on chromosome 8q24.21. Recent research works have revealed that CASC19 is involved in the prognosis of tumors and related to the regulation of the radiation tolerance mechanisms during tumor radiotherapy (RT). This review sheds light on the changes and roles that CASC19 plays in many tumors and diseases, such as nasopharyngeal carcinoma (NPC), cervical cancer, colorectal cancer (CRC), non-small cell lung cancer (NSCLC), clear cell renal cell carcinoma (ccRCC), gastric cancer (GC), pancreatic cancer (PC), hepatocellular carcinoma (HCC), glioma, and osteoarthritis (OA). CASC19 provides a new strategy for targeted therapy, and the regulatory networks of CASC19 expression levels play a key role in the occurrence and development of tumors and diseases. In addition, the expression level of CASC19 has predictive roles in the prognosis of some tumors and diseases, which has major implications for clinical diagnoses and treatments. CASC19 is also unique in that it is a key gene affecting the efficacy of RT in many tumors, and its expression level plays a decisive role in improving the success rate of treatments. Further research is required to determine the precise process by which CASC19 causes changes in diseased cells in some tumors and diseases.

Rational design, synthesis and biological evaluation of novel HIV-1 protease inhibitors containing 2-phenylacetamide derivatives as P2 ligands with potent activity against DRV-Resistant HIV-1 variants.

A novel kind of potent HIV-1 protease inhibitors, containing diverse hydroxyphenylacetic acids as the P2-ligands and 4-substituted phenyl sulfonamides as the P2' ligands, were designed, synthesized and evaluated in this work. Majority of the target compounds exhibited good to excellent activity against HIV-1 protease with IC50 values below 200 nM. In particular, compound 18d with a 2-(3,4-dihydroxyphenyl) acetamide as the P2 ligand and a 4- methoxybenzene sulfonamide P2' ligand exhibited inhibitory activity IC50 value of 0.54 nM, which was better than that of the positive control darunavir (DRV). More importantly, no significant decline of the potency against HIV-1DRVRS (DRV-resistant mutation) and HIV-1NL4_3 variant (wild type) for 18d was detected. The molecular docking study of 18d with HIV-1 protease (PDB-ID: 1T3R, www.rcsb.org) revealed possible binding mode with the HIV-1 protease. These results suggested the validity of introducing phenol-derived moieties into the P2 ligand and deserve further optimization which was of great value for future discovery of novel HIV-1 protease.

Application of Nanomedicine in Tumor Targeting Inflammatory Pathway.

Given the threat of ever-growing cancer morbidity, it is a cutting-edge frontier for multiple disciplines to apply nanotechnology in cancer therapy. Nanomedicine is now perpetually influencing the diagnosis and treatment of cancer. Meanwhile, tumorigenesis and cancer progression are intimately associated with inflammation. Inflammation can implicate in various tumor progression via the same or different pathways. Therefore, current nanomedicines exhibit tumor-suppressing function through inflammatory pathways. At present, the comprehensive understanding and research on the mechanism of various nanoparticles in cancer treatment are still in progress. In this review, we summarized the applications of nanomedicine in tumor-targeting inflammatory pathways, suggesting that nanoparticles could be a budding star for cancer therapy.

Regulation of tumor metastasis and CD8+ T cells infiltration by circRNF216/miR-576-5p/ZC3H12C axis in colorectal cancer.

BACKGROUND: The tumor immune microenvironment (TIME) is an important regulator of tumor progression, growth and metastasis. In addition, tumor metastasis is one of the principal obstacles to the treatment of colorectal cancer (CRC). Circular RNAs (circRNAs) have been recognized as important regulators in the development of malignancies. However, their specific roles and mechanisms in both CRC metastasis and TIME have not been thoroughly investigated. METHODS: High-throughput next-generation sequencing technology and real-time fluorescence quantitative PCR technology were performed to identify differential circRNAs in CRC. Functional assays including transwell assay, wound healing assay, and metastasis models were conducted to assess the effect of circRNF216 on CRC metastasis. In addition, luciferase reporter, western blot, RNA immunoprecipitation (RIP), and fluorescent in situ hybridization (FISH) were performed to explore the underlying mechanism of circRNF216. The level of immune infiltration was assessed by bioinformatics analysis and flow cytometry in CRC model. Furthermore, rescue and mutation experiments were used for verification. RESULTS: circRNF216 was identified as a putative tumor suppressor that is downregulated in CRC tissues and cells. Overexpression of circRNF216 inhibits metastasis in vitro and vivo. Mechanistically, circRNF216 acts as a competitive endogenous RNA (ceRNA) for miR-576-5p, alleviating miR-576-5p repression on its target ZC3H12C, which in turn downregulated N-cadherin. Additionally, circRNF216 could enhance the infiltration level of CD8+ T cells by upregulating ZC3H12C, ultimately inhibiting the development of CRC, which suggests that circRNF216 is a potential biomarker for the treatment of CRC. CONCLUSIONS: Here, we provide novel mechanistic insight revealing how circRNF216 functioned in CRC metastasis and TIME via the circRNF216/miR-576-5p/ZC3H12C pathway. Therefore, circRNF216 holds promise as a potential therapeutic target and novel diagnostic marker for CRC.

Association of LncRNA PCBP1-AS1 with cancer occurrence and development: A review.

Long-stranded noncoding RNAs (LncRNAs) are noncoding RNAs >200 nucleotides in length. Polycytidine binding protein 1 antisense LncRNA is abbreviated as LncRNA polycytosine binding protein 1 antisense1 (PCBP1-AS1). Since studies in recent years have revealed the importance of PCBP1-AS1 in human genetic analysis, it is an important member of the LncRNA family. Genetically engineered group analysis of PCBP1-AS1 regulates the progression of cancer in biology. Therefore, it may be an important RNA in the regulation of human cancer. This article summarizes the molecular mechanism and clinical role of PCBP1-AS1 in various tumor types. Taking "PCBP1-AS1" and "cancer" as keywords, this paper analyzed the relationship between PCBP1-AS1 and various tumors by searching PubMed and Geen Medical, and summarized the related regulatory mechanism of PCBP1-AS1. PCBP1-AS1 is a valuable tumor-associated LncRNA that plays different biological roles in different cancers. Overall, it can both promote and inhibit the development of cancer. For example, abnormally high expression in castration-resitant prostate cancer, hepatocellular carcinoma, cervical cancer, glioma, and colorectal cancer promotes the proliferation and progression of these cancers; in contrast, PCBP1-AS1 inhibits cancer proliferation, metastasis, invasion, and recurrence when highly expressed in vulvar squamous cell carcinoma, Hodgkin lymphoma, and lung adenocarcinoma. PCBP1-AS1 regulates the development of multiple tumors, and the specific mechanism needs to be further investigated, which may become a new tumor marker and potential therapeutic target.

HPV E7-drived ALKBH5 promotes cervical cancer progression by modulating m6A modification of PAK5.

Human papillomavirus (HPV) infection is a causative agent of cervical cancer (CC). N6-methyladenosine (m6A) modification is implicated in carcinogenesis and tumor progression. However, the involvement of m6A modification in HPV-involved CC remains unclear. Here we showed that HPV E6/7 oncoproteins affected the global m6A modification and E7 specifically promoted the expression of ALKBH5. We found that ALKBH5 was significantly upregulated in CC and might serve as a valuable prognostic marker. Forced expression of ALKBH5 enhanced the malignant phenotypes of CC cells. Mechanistically, we discovered that E7 increased ALKBH5 expression through E2F1-mediated activation of the H3K27Ac and H3K4Me3 histone modifications, as well as post-translational modification mediated by DDX3. ALKBH5-mediated m6A demethylation enhanced the expression of PAK5. The m6A reader YTHDF2 bound to PAK5 mRNA and regulated its stability in an m6A-dependent manner. Moreover, ALKBH5 promoted tumorigenesis and metastasis of CC by regulating PAK5. Overall, our findings herein demonstrate a significant role of ALKBH5 in CC progression in HPV-positive cells. Thus, we propose that ALKBH5 may serve as a prognostic biomarker and therapeutic target for CC patients.

Alginate Oligosaccharides Enhance Autophagy to Rejuvenate H2O2-Induced Senescent IEC-6 Through the AMPK/mTOR Signaling Pathway.

Intestinal epithelial cellular senescence contributes to the physiological decline of intestine and induces age-associated intestinal diseases. Therefore, the intestine is a vital target to delay intestinal epithelial cellular senescence and extend healthy lifespan. Alginate oligosaccharides (AOSs) have a wide range of biological and pharmacological activities. However, there are no related reports of AOSs on intestinal epithelial cellular senescence. Our study aimed to investigate the effect of AOSs on hydrogen peroxide (H2O2)-induced senescent intestinal epithelial cells (IEC-6) and its antiaging mechanism. A senescent model was successfully constructed by H2O2 (200 µmol/L) treatment on IEC-6 for 4 hours. Different concentrations of AOSs (10, 50, 100 µg/mL) were used to intervene in H2O2-induced senescent IEC-6. The number of ß-galactosidase staining-positive cells was significantly reduced by AOS intervention. The expression levels of p21 and p16, known as the senescent biomarkers, were also decreased. In addition, AOSs alleviated oxidative stress by reducing reactive oxygen species and improving antioxidative ability. To understand how AOSs rejuvenate H2O2-induced senescent IEC-6, we detected the expression level of genes in autophagy process. The results indicated that AOSs restored the expression level of Beclin 1, Atg7, and LC3 to enhance autophagy process by activating activated protein kinase (AMPK) and inhibiting mammalian target of rapamycin in H2O2-induced senescent IEC-6. Compound C, an AMPK inhibitor, abolished the effect of AOSs on activating autophagy and rejuvenating senescent IEC-6. Altogether, our study suggests that AOS is a promising drug for delaying intestinal epithelial cellular senescence.

The Functions of EphA1 Receptor Tyrosine Kinase in Several Tumors.

BACKGROUND: Eph receptors tyrosine kinase (RTK) were identified in 1987 from hepatocellular carcinoma cell lines and were the largest known subfamily of RTK. Eph receptors can be divided into two categories, EphA and EphB, based on their structure and receptor-ligand specificity. EphA can be divided into 10 species (EphA 1-10) and EphB into 6 species (EphB1-6). Similarly, the ligands of Eph receptors are Ephrins. Ephrins also can be divided into Ephrin A and Ephrin B, of which there are five species(Ephrin-A1-5) and three species(Ephrin-B1-3). Among the Eph receptors, EphA1 has been the least studied so far. As far as we know, Eph receptors are involved in multiple pathologies, including cancer progression, tumor angiogenesis, intestinal environmental stability, the lymph node system, neurological disease, and inhibition of nerve regeneration after injury. There is a link between EphA1, integrin and ECM- related signal pathways. Ephrin-A1 is a ligand of the EphA1 receptor. EphA1 and ephrin-A1 functions are related to tumor angiogenesis. EphA1 and ephrin-A1 also play roles in gynecological diseases. Ephrin-A1 and EphA1 receptors regulate the follicular formation, ovulation, embryo transport, implantation and placental formation, which are of great significance for the occurrence of gynecological tumor diseases. EphA1 has been identified as an oncoprotein in various tumors and has been associated with the prognosis of various tumors in recent years. EphA1 is considered a driver gene in tumor genomics. There are significant differences in EphA1 expression levels in different types of normal tissues and tumors and even in different stages of tumor development, suggesting its functional diversity. Changes at the gene level in cell biology are often used as biological indicators of cancer, known as biomarkers, which can be used to provide diagnostic or prognostic information and are valuable for improving the detection, monitoring and treatment of tumors. However, few prognostic markers can selectively predict clinically significant tumors with poor prognosis. These malignancies are more likely to progress and lead to death, requiring more aggressive treatment. Currently available treatments for advanced cancer are often ineffective, and treatment options are mainly palliative. Therefore, early identification and treatment of those at risk of developing malignant tumors are crucial. Although pieces of evidence have shown the role of EphA1 in tumorigenesis and development, its specific mechanism is still unknown to a great extent. OBJECTIVE: This review reveals the changes and roles of EphA1 in many tumors and cancers. The change of EphA1 expression can be used as a biological marker of cancer, which is valuable for improving tumor detection, monitoring and treatment and can be applied to imaging. Studies have shown that structural modification of EphA1 could make it an effective new drug. EphA1 is unique in that it can be considered a prognostic marker in many tumors and is of important meaning for clinical diagnosis and operative treatment. At the same time, the study of the specific mechanism of EphA1 in tumors can provide a new way for targeted therapy. METHODS: Relevant studies were retrieved and collected through the PubMed system. After determining EphA1 as the research object, by analyzing research articles on EphA1 in the PubMed system in recent 10 years, we found that EphA1 was closely connected with the occurrence and development of tumors and further determined the references according to the influencing factors for review and analysis. RESULTS: EphA1 has been identified as a cancer protein in various tumors, such as hepatocellular carcinoma, nasopharyngeal carcinoma, ovarian cancer, gastric cancer, colorectal cancer, clear cell renal cell carcinoma, esophageal squamous cell carcinoma, breast cancer, prostate cancer and uveal melanoma. EphA1 is abnormally expressed in these tumor cells, which mainly plays a role in cancer progression, tumor angiogenesis, intestinal environmental stability, the lymph node system, nervous system diseases and gynecological diseases. In a narrow sense, EphA1 is especially effective in breast cancer in terms of gynecological diseases. However, the specific mechanism of EphA1 leading to the change of cancer cells in some tumors is not clear, which needs further research and exploration. CONCLUSION: RTK EphA1 can be used as a biomarker for tumor diagnosis (especially a prognostic marker), an indispensable therapeutic target for new anti-tumor therapies, and a novel anti-tumor drug.

WDFY3-AS2: A Potential Prognostic Factor and Therapeutic Target Related to Cancer.

BACKGROUND: Abundant studies have shown that non-coding RNA is connected with tumor cell growth, migration and invasion. As a newly discovered non-coding RNA, WDFY3-AS2 has gradually emerged in the molecular mechanism of various tumors and has a potential prospect as a biological indicator of tumor prognosis. This review describes the pathophysiological mechanism and prognostic value of WDFY3-AS2 in different cancers. OBJECTIVE: This review reveals the changes and roles of WDFY3-AS2 in many tumors and cancers. The change of WDFY3-AS2 can be used as a cancer biomarker and plays an important role in improving tumor growth, migration and invasion. WDFY3-AS2 is unique because it can be considered a prognostic marker for many tumors and is of great significance for clinical diagnosis and treatment. WDFY3-AS2 shows the potential prognostic value and the prospect of therapeutic targets in various tumors. METHODS: PubMed reviewed the related literature to analyze and summarize the regulatory molecular mechanism of WDFY3-AS2 in various tumors and its value as a prognostic indicator. RESULTS: The abnormal expression of LncRNA WDFY3-AS2 in many cancers was connected with the poor prognosis of cancer patients, including diffuse glioma, hepatocellular carcinoma, ovarian cancer, esophageal cancer, triple-negative breast cancer, Clear Cell Renal Carcinoma, Esophageal squamous cell carcinoma, Lung adenocarcinoma, which participated in the recovery of orthodontic teeth. WDFY3-AS2 has revealed the cellular process of cancer cell growth, migration, and invasion. CONCLUSION: The molecular mechanism of LncRNA WDFY3-AS2 regulating tumor specifically proves that WDFY3-AS2 has a good prospect in the biological index of prognosis or clinical treatment target of cancer patients.

MIR4435-2HG: A Tumor-associated Long Non-coding RNA.

BACKGROUND: It is well known that the changes in the expression level of LncRNA can affect the progression of tumors, which has caused a great upsurge of research in recent years. Several LncRNAs have been identified to affect a series of cancers and can promote tumor growth, migration, and invasion. In this review, we aim to clarify the pathophysiological functions of LncRNA MIR4435-2 HG in multiple tumors. METHODS: By searching the literature through PubMed, this paper summarizes the relationship between MIR4435-2HG and tumor and its role in the occurrence and development of cancer and also explains the specific molecular mechanism of the effect of MIR4435-2HG on cancer. RESULTS: MIR4435-2HG can function as an oncogene in a variety of cancers. The expression level was reported to be abnormally elevated in a series of cancers, consisting of melanoma, gastric cancer, head and neck squamous cell carcinoma, oral squamous cell carcinoma, lung cancer, cervical cancer, prostate carcinoma, ovarian cancer, breast cancer, hepatocellular carcinoma, clear cell renal cell carcinoma malignant, glioma, and colorectal cancer. Moreover, MIR4435-2HG is related to the poor prognosis of a variety of cancers. MIR4435-2HG can also affect tumor proliferation, invasion, and apoptosis. In addition, MIR4435-2HG can also enhance the metabolic function of myeloid dendritic cells of elite HIV-1 controllers. CONCLUSION: MIR4435-2HG affects the development of a variety of cancers. It can act as a clinical marker for early tumor diagnosis and affects tumor-targeted therapy.

HNF1A-AS1: A Tumor-associated Long Non-coding RNA.

BACKGROUND: Hepatocyte nuclear factor 1 homeobox A antisense RNA 1 (HNF1A-AS1) is a Long non-coding RNA (LncRNA) that participates in the occurrence and development of lots of tumors and is supposed to be a new biomarker. The text aims to illustrate the biological effect, specific mechanism and clinical significance of HNF1A-AS1 in various tumors. METHODS: Via consulting the literature, analyze and summarize the relationship between HNF1A-AS1 and all kinds of tumors and the specific mechanism. RESULTS: This is a review paper about the tumor-associated long non-coding RNA HNF1A-AS1. Many researches show that LncRNA HNF1A-AS1 is related to the development of tumorous tumors. Its expression is up-regulated in numerous tumors, such as oral squamous cell carcinoma, hepatocellular carcinoma, breast cancer, osteosarcoma, lung cancer, cervical cancer, bladder cancer, colon cancer, colorectal cancer, oesophageal adenocarcinoma and laryngeal squamous cell carcinoma. However, HNF1A-AS1 is down-regulated in gastroenteropancreatic, neuroendocrine neoplasms, oral squamous cell carcinoma. Furthermore, HNF1A-AS1 can affect tumor proliferation, invasion, migration and apoptosis by targeting some microRNAs-miR-661 and miR-124. HNF1A-AS1 can also influence the development of tumors by regulating EMT. CONCLUSION: These studies show that LncRNA-HNF1A-AS1 is closely related to the occurrence development of numerous cancers. Through various molecular mechanisms to regulate tumor growth, HNF1A-AS1 can possibly become the new biological biomarker and therapeutic target for many kinds of tumors.

LncRNA SBF2-AS1: A Budding Star in Various Cancers.

Long non-coding RNA (lncRNA) is a new kind of RNA with a length of over 200 nucleotides. Current frontiers revealed that lncRNAs implicate in various tumor progression, including tumorigenesis, proliferation, migration, invasion, metastasis, and angiogenesis. Recently discovered long non-coding RNA SETbinding factor 2 antisense RNA 1 (lncRNA SBF2-AS1), an oncogenic antisense RNA to SBF2, locates at 11p15.1 locus and is 2708 nt long. Accumulating evidence has demonstrated that lncRNA SBF2-AS1 participates in the progression of the various tumor, including pathogenesis, diagnosis, treatment, and prognosis of acute myeloid leukemia (AML), breast cancer (BC), cervical cancer (CC), clear cell renal cell carcinoma (ccRCC), colorectal cancer (CRC), diffuse large B-cell lymphoma (DLBCL), esophageal squamous cell carcinoma (ESCC), gastric cancer (GC), glioma, glioblastoma (GBM), hepatocellular carcinoma (HCC), lung cancer (LC), lung adenocarcinoma (LUAD), non-small cell lung cancer (NSCLC), osteosarcoma (OS), pancreatic cancer (PC), papillary thyroid cancer (PTC), small cell lung cancer (SCLC). Therefore, we summarized the underlying mechanisms of lncRNA SBF2-AS1 in various cancers to utilize its therapeutic function in target-selective treatment modalities.

FER1L4: A Long Non-coding RNA with Multiple Roles in the Occurrence and Development of Tumors.

BACKGROUND: FER-1 family member 4 (FER1L4), a 6.7 kb lncRNA located at 20q11.22, plays an important biological function in a variety of tumor diseases. The purpose of this review is to clarify the pathophysiological mechanism and potential biological function of FER1L4 in different tumors. METHODS: By searching the relevant literature in PubMed, the specific pathophysiological mechanism of FER1L4 in different tumors was summarized. RESULTS: LncRNA FER1L4 is one of the key factors in tumorigenesis and is abnormally down-regulated in many tumors, including osteosarcoma, lung cancer, laryngeal squamous cell carcinoma, laryngeal cancer, colorectal cancer, ovarian cancer, prostate cancer, esophageal cancer, gastric cancer, endometrial cancer, osteoarthritis, rheumatoid arthritis, and so on. However, FER1L4 is downregulated in breast cancer, glioma, oral squamous cell carcinoma, renal clear cell carcinoma, and periodontitis, and plays a protective role in orthodontic teeth. In addition, as a tumor suppressor gene or oncogene, FER1L4 affects tumor proliferation, invasion, migration, and apoptosis. CONCLUSION: LncRNA FER1L4 has a good application prospect in the treatment and diagnosis of various tumors.

The Regulatory Role of Both MBNL1 and MBNL1-AS1 in Several Common Cancers.

BACKGROUND: Muscle blind-like-proteins (MBNL) are a class of tissue-specific RNA metabolism regulators that control pre-messenger RNA-splicing. Inactivation of MBNL can lead to myotonic dystrophy in adults. MBNL is mainly expressed in skeletal muscle, neuron tissue, thymus, liver, and kidney and plays an important role in the ultimate differentiation of muscle cells and neurons. MBNL1 is a member of the MBNL protein family. The inactivation of MBNL1 protein is particularly important in the development of myotonic dystrophy and can lead to cataract formation, abnormal muscle relaxation, cardiac and neurological dysfunction, etc. The induction of MBNL1 in tumors is known to significantly inhibit tumor progression and thus significantly prolong survival. MBNL1 antisense protein MBNL1-AS1 also plays an important role in tumor migration and development. OBJECTIVE: This review reveals the role of MBNL1 and MBNL1-AS1 in the complex pathogenesis of many tumors, which provide a new target for the treatment of tumors. METHODS: Correlated research are systematically retrieved via PubMed. In this review, the role of MBNL1 and MBNL1- AS1 were analyzed. RESULTS: MBNL1 is down-regulated in breast cancer, leukemia, stomach cancer, esophageal cancer, glioma, and Huntington's disease. The function of inhibiting tumor cell metastasis decreased. It is up-regulated in cervical cancer and colorectal cancer, which can promote the development of tumor cells. Antisense protein MBNL1- AS1 can inhibit tumor cell proliferation and metastasis in colorectal cancer, non-small cell lung cancer, and gastric cancer. CONCLUSION: MBNL1 is an important regulator of tumor metastasis and growth, which exhibits a promising therapeutic target and can be further explored.

MicroRNA-138-1-3p sensitizes sorafenib to hepatocellular carcinoma by targeting PAK5 mediated ß-catenin/ABCB1 signaling pathway.

BACKGROUND: Sorafenib is a kinase inhibitor that is used as a first-line therapy in advanced hepatocellular carcinoma (HCC) patients. However, the existence of sorafenib resistance has limited its therapeutic effect. Through RNA sequencing, we demonstrated that miR-138-1-3p was downregulated in sorafenib resistant HCC cell lines. This study aimed to investigate the role of miR-138-1-3p in sorafenib resistance of HCC. METHODS: In this study, quantitative real-time PCR (qPCR) and Western Blot were utilized to detect the levels of PAK5 in sorafenib-resistant HCC cells and parental cells. The biological functions of miR-138-1-3p and PAK5 in sorafenib-resistant cells and their parental cells were explored by cell viability assays and flow cytometric analyses. The mechanisms for the involvement of PAK5 were examined via co-immunoprecipitation (co-IP), immunofluorescence, dual luciferase reporter assay and chromatin immunoprecipitation (ChIP). The effects of miR-138-1-3p and PAK5 on HCC sorafenib resistant characteristics were investigated by a xenotransplantation model. RESULTS: We detected significant down-regulation of miR-138-1-3p and up-regulation of PAK5 in sorafenib-resistance HCC cell lines. Mechanistic studies revealed that miR-138-1-3p reduced the protein expression of PAK5 by directly targeting the 3'-UTR of PAK5 mRNA. In addition, we verified that PAK5 enhanced the phosphorylation and nuclear translocation of ß-catenin that increased the transcriptional activity of a multidrug resistance protein ABCB1. CONCLUSIONS: PAK5 contributed to the sorafenib resistant characteristics of HCC via ß-catenin/ABCB1 signaling pathway. Our findings identified the correlation between miR-138-1-3p and PAK5 and the molecular mechanisms of PAK5-mediated sorafenib resistance in HCC, which provided a potential therapeutic target in advanced HCC patients.

METTL3-mediated m6A methylation of SPHK2 promotes gastric cancer progression by targeting KLF2.

N6-methyladenosine (m6A) RNA methylation is profoundly involved in epigenetic regulation, especially for carcinogenesis and tumor progression. Mounting evidence suggests that methyltransferase METTL3 regulates malignant behaviors of gastric cancer (GC). However, the clinical significance and biological implication of SPHK2 and its related m6A modification in GC remain unclear. In this study, quantitative real-time PCR (qRT-PCR), western blot and immunohistochemistry were utilized to detect the expression profiles and prognostic significance of SPHK2 in GC. Here, we showed that increased SPHK2 was signified a poor prognosis of GC patients. Phosphorylation and ubiquitination assays were used to investigate the possible mechanisms of SPHK2-mediated KLF2 expression. SPHK2 can promote the phosphorylation of KLF2, which triggers the ubiquitination and degradation of KLF2 protein in GC. Methylated RNA immunoprecipitation (MeRIP) was performed to uncover the m6A modification of SPHK2 mRNA. METTL3 promotes translation of SPHK2 mRNA via an m6A-YTHDF1-dependent manner. Functionally, SPHK2 facilitates GC cell proliferation, migration and invasion by inhibiting KLF2 expression. SPHK2/KLF2 regulates the cell proliferation, migration, and invasion induced by METTL3 in GC. Overall, our findings reveal that METTL3-mediated m6A modification of SPHK2 contributes to GC progression, which extends the understanding of the importance m6A methylation in GC and represents a potential target for GC therapy.

Epidermal growth factor-like domain multiple 6 (EGFL6) promotes the migration and invasion of gastric cancer cells by inducing epithelial-mesenchymal transition.

Epidermal growth factor-like domain multiple 6 (EGFL6) is implicated in tumor growth, metastasis and angiogenesis, and its ectopic alteration has been detected in aggressive malignancies. However, the pathophysiologic roles and molecular mechanisms of EGFL6 in gastric cancer (GC) remain to be elucidated. In this study, we investigated EGFL6 expression in GC cell lines and tissues using western blotting and immunohistochemistry. We found that EGFL6 was elevated expression in GC cell lines and tissues. The high expression of EGFL6 significantly was correlated with histological grade, depth of invasion, lymph node involvement, distant metastasis and TNM stage in GC and predicted poorer prognosis, and it could act an independent prognostic factor for GC patients. EGFL6 enhanced the proliferation, migration and invasion of GC cells. In addition, we identified the possible molecular mechanisms of EGFL6-involved epithelial-mesenchymal transition (EMT). EGFL6 regulated EMT process and induced metastasis partly through FAK/PI3K/AKT/mTOR, Notch and MAPK signaling pathways. In conclusion, EGFL6 confers an oncogenic function in GC progression and may be proposed as a potential therapeutic target for GC.

CSN6 promotes the cell migration of breast cancer cells by positively regulating Snail1 stability.

Background: CSN6, a subunit of the highly conserved constitutive photomorphogenesis 9 (COP9) signalosome (CSN), has been reported to be implicated in tumor progression in various kinds of malignant tumors. However, the mechanism underlying CSN6 in the tumor development of breast cancer has not yet been fully elucidated. Methods: CSN6 staining in breast cancer tissues and paracancerous tissues was measured by tissue microarray (TMA) technology. The metastatic effect of CSN6 was measured by cell migration assay. Co-immunoprecipitation study was used to show the interaction between the protein CSN6 and Snail1. Ubiquitination assay was performed to validate whether ubiquitination is involved in the upregulation of Snail1 by CSN6. The impact of CSN6 on tumor metastasis in vivo was analyzed using xenotransplantation experiments in BALB/c mice. Results: Here, we demonstrated that CSN6 expression was dramatically increased in breast cancer tissues compared with paired adjacent cancerous tissues. CSN6 promoted the cell migration and wound healing abilities in breast cancer cell lines. Also we showed that CSN6 associates with Snail1 and enhances Snail1 protein level by inhibiting the ubiquitin-mediated degradation of Snail1. Thus, CSN6 is involved in positively regulating the stability of Snail1. We further proved that CSN6 protein level was positively correlated with the Snail1 expression in xenograft model. Conclusion: These findings provide new insight into applicability of using the CSN6-Snail1 axis as a potential therapeutic target in breast cancer.