Recent findings on miR­370 expression, regulation and functions in cancer (Review).

MicroRNAs (miRNAs/miRs) are a group of small non­coding RNAs that serve as post­transcriptional gene modulators. miRNAs have been demonstrated to serve a pivotal role in carcinogenesis and the dysregulated expression of miRNAs is a well­understood characteristic of cancer. In recent years, miR­370 has been established as a key miRNA in various cancers. The expression of miR­370 is dysregulated in various types of cancer and varies markedly across different tumor types. miR­370 can regulate multiple biological processes, including cell proliferation, apoptosis, migration, invasion, as well as cell cycle progression and cell stemness. Moreover, it has been reported that miR­370 affects the response of tumor cells to anticancer treatments. Additionally, the expression of miR­370 is modulated by multiple factors. The present review summarizes the role and mechanism of miR­370 in tumors, and demonstrates its potential as a molecular marker for cancer diagnosis and prognosis.

CCL19 has potential to be a potential prognostic biomarker and a modulator of tumor immune microenvironment (TIME) of breast cancer: a comprehensive analysis based on TCGA database.

The development of cancer was determined by not only the intrinsic properties of cancer cells, but also the communication between cancer cells and tumor microenvironment (TME). We applied ESTIMATE and CIBERSORT algorithms to calculate the immune/stromal component and tumor-infiltrating immune cells (TICs) in TME of BC. The results showed that immune component in TME predicted patients' survival and associated with progression of BC. Differentially expressed genes (DEGs) were primarily enriched in immune-related activities. Finally, CCL19 was acquired which shared the leading nodes in PPI network and was associated with patients' survival. High expression of CCL19 predicted better prognosis and participated in progression of BC. Genes in CCL19 up-regulated group were enriched in immune-related activities and these functions might depend on the communications between CCL19 and multiple TICs in TIME. In conclusion, CCL19 functioned as a potential prognostic biomarker and a modulator of TIME in BC through communicating with various TICs.

Functions and Targets of miR-335 in Cancer.

MicroRNAs (miRNAs) are small non-coding RNAs (18~25 nt in length) that act as master regulators of eukaryotic gene expression. They might play an oncogenic or tumor-suppressive role in multiple cancers. In recent decades, several studies have focused on the functions and mechanisms of miR-335 in cancer. The expression level of miR-335 in tissues and cells varies with cancer types, and miR-335 has been proposed as a potential biomarker for the prognosis of cancer. Besides, miR-335 may serve as an oncogene or tumor suppressor via regulating different targets or pathways in tumor initiation, development, and metastasis. Furthermore, miR-335 also influences tumor microenvironment and drug sensitivity. MiR-335 is regulated by various factors such as lncRNAs and microRNAs. In this review, we reveal the functions and targets of miR-335 in various cancers and its potential application as a possible biomarker in prognostic judgment and treatment of malignant tumors.

TGFß1: An Indicator for Tumor Immune Microenvironment of Colon Cancer From a Comprehensive Analysis of TCGA.

BACKGROUND: Tumor microenvironment (TME) and tumor-infiltrating immune cells (TICs) greatly participate in the genesis and development of colon cancer (CC). However, there is little research exploring the dynamic modulation of TME. METHODS: We analyzed the proportion of immune/stromal component and TICs in the TME of 473 CC samples and 41 normal samples from The Cancer Genome Atlas (TCGA) database through ESTIMATE and CIBERSORT algorithms. Correlation analysis was conducted to evaluate the association between immune/stromal component in the TME and clinicopathological characteristics of CC patients. The difference analysis was performed to obtain the differentially expressed genes (DEGs). These DEGs were further analyzed by GO and KEGG enrichment analyses, PPI network, and COX regression analysis. Transforming growth factor ß1 (TGFß1) was finally overlapped from the above analysis. Paired analysis and GSEA were carried out to understand the role of TGFß1 in colon cancer. The intersection between the difference analysis and correlation analysis was conducted to learn the association between TGFß1 and TICs. RESULTS: Our results showed that the immune component in the TME was negatively related with the stages of CC. GO and KEGG enrichment analysis revealed that 1,110 DEGs obtained from the difference analysis were mainly enriched in immune-related activities. The intersection analysis between PPI network and COX regression analysis indicated that TGFß1 was significantly associated with the communication of genes in the PPI network and the survival of CC patients. In addition, TGFß1 was up-regulated in the tumor samples and significantly related with poor prognosis of CC patients. Further GSEA suggested that genes in the TGFß1 up-regulated group were enriched in immune-related activities and the function of TGFß1 might depend on the communications with TICs, including T cells CD4 naïve and T cells regulatory. CONCLUSION: The expression of TGFß1 might be an indicator for the tumor immune microenvironment of CC and serve as a prognostic factor. Drugs targeting TGFß1 might be a potential immunotherapy for CC patients in the future.

The biological function of m6A demethylase ALKBH5 and its role in human disease.

Human AlkB homolog H5 (ALKBH5) is a primary m6A demethylase, which is dysregulated and acts as a biological and pharmacological role in human cancers or non-cancers. ALKBH5 plays a dual role in various cancers through regulating kinds of biological processes, such as proliferation, migration, invasion, metastasis and tumor growth. In addition, it takes a great part in human non-cancer, including reproductive system diseases. The underlying regulatory mechanisms of ALKBH5 that relys on m6A-dependent modification are implicated with long non-coding RNA, cancer stem cell, autophagy and hypoxia. ALKBH5 is also an independent prognostic indicator in various cancers. In this review, we summarized the current evidence on ALKBH5 in diverse human cancers or non-cancers and its potential as a prognostic target.

Potential regulatory role of lncRNA-miRNA-mRNA axis in osteosarcoma.

Osteosarcoma (OS) is one of the most common malignant bone tumors in childhood and adolescence. Although great efforts have been made in therapeutic methods for OS, the prognosis is not yet satisfactory and the underlying molecular mechanisms of OS pathogenesis have not been fully explored. Meanwhile, non-coding RNAs, especially microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), have long been investigated due to their roles as key players in regulating various biological and pathological processes, such as proliferation, apoptosis, cell-cycle, migration, invasion, metastasis, EMT and drug resistance, through targeting their mRNAs transcriptionally or posttranscriptionally. Although, numerous studies have confirmed a complex cross-regulation among lncRNAs, miRNAs and mRNAs, the underlying molecular mechanism has not been elucidated. In this review, we comprehensively summarized the latest research progress of the regulatory relationship among lncRNAs, miRNAs and mRNAs, and highlighted the role of lncRNA-miRNA-mRNA axis in the development of OS to provide novel approaches for cancer diagnosis and treatment.

Long Noncoding RNA SBF2-AS1 Is Critical for Tumorigenesis of Early-Stage Lung Adenocarcinoma.

Emerging evidence demonstrates that long non-coding RNAs (lncRNAs) are deeply involved in the development of various cancers. This study identified that SBF2-AS1, an early-stage-specific lncRNA, is critical for the tumorigenesis of lung adenocarcinoma (LUAD). We first analyzed LUAD transcriptome data from The Cancer Genome Atlas and the GEO database by weighted gene co-expression network analysis (WGCNA). Five early LUAD-specific lncRNAs were filtered out, and only SBF2-AS1 was upregulated in LUAD. High expression of SBF2-AS1 indicates poor survival of LUAD, especially the early-stage LUAD, but not lung squamous cell carcinoma. SBF2-AS1 promotes LUAD cells proliferation in vitro, and RNA-sequencing data shows that many cell-cycle-related genes were downregulated after SBF2-AS1 knockdown. Mechanically, SBF2-AS1 could competitively bind with miR-338-3p and miR-362-3p to increase E2F1 expression. Finally, we show that the SBF2-AS1-miR-338-3p/362-3p-E2F1 axis could promote LUAD tumorigenesis in vitro and in vivo. Our study demonstrates that SBF2-AS1, an early-stage-specific lncRNA, promotes LUAD tumorigenesis by sponging miR-338-3p and miR-362-3p and increasing E2F1 expression. The SBF2-AS1-miR-338-3p/362-3p-E2F1 regulatory axis may serve as a prognostic marker and potential therapeutic target for LUAD.

Synthesis of novel galactose functionalized gold nanoparticles and its radiosensitizing mechanism.

BACKGROUND: Biocompatible gold nanoparticles (GNPs) are potentially practical and efficient agents in cancer radiotherapy applications. In this study, we demonstrated that GNPs can significantly modulate irradiation response of hepatocellular carcinoma cells in vitro and investigated the underlying mechanisms. We co-grafted galactose (GAL) targeting hepatocyte specific asialoglycoprotein receptor and Polyethylene Glycol (PEG) onto GNPs surfaces to increase GNPs targeting specificity and stability. RESULTS: This novel GAL-PEG-GNPs and bare GNPs show similar appearance and cytotoxicity profiles, while more GAL-PEG-GNPs can be effectively uptaken and could enhance cancer cell killing. CONCLUSION: GAL-PEG-GNPs have better radiosensitization to HepG2. The sensitization mechanism of GAL-PEG-GNPs is related to the apoptotic gene process activated by generation of a large amount of free radicals induced by GNPs.

[Objective evaluation of otolithic end organs in sudden sensorineural hearing loss patients].

OBJECTIVE: To observe the function of the otolithic end organs and their input pathways in sudden sensorineural hearing loss (SSHL) patients. METHODS: Forty cases of unilateral SSHL were enrolled as the observing group from May, 2011 to May, 2012. Thirty age- and gender-matched normal subjects were recruited as the control group. Both patients and normal subjects underwent conventional air-conducted ocular vestibular evoked myogenic potential (oVEMP) and cervical vestibular evoked myogenic potential (cVEMP) in bilateral ears. The results were compared between the affected ears, the contralateral ears and the normal controls. RESULTS: Overall, oVEMP was elicited in 16 affected ears (40.0%), 23 contralateral ears (57.5%) and 43 normal ears (71.7%). cVEMP could be elicited in 25 affected ears (62.5%), 30 contralateral ears (75.0%) and 49 normal ears (81.7%) respectively. Significant statistical significance could be found in the oVEMP response rate between the affected ears and the normal ears (χ(2) = 9.949, P = 0.002) and in the cVEMP response rate between the affected ears and the normal ears (χ(2) = 4.582, P = 0.032). Significant statistical difference could not be found in all oVEMP and cVEMP parameters (threshold, N1 latency, P1 latency, latency interval and amplitude) among groups (P > 0.05). CONCLUSIONS: The otolithic vestibular end organs and their input pathways could be damaged in SSHL patients. Such damages could be monitored objectively by cVEMP and oVEMP examinations.

An oncolytic adenovirus regulated by a radiation-inducible promoter selectively mediates hSulf-1 gene expression and mutually reinforces antitumor activity of I131-metuximab in hepatocellular carcinoma.

Gene therapy and antibody approaches are crucial auxiliary strategies for hepatocellular carcinoma (HCC) treatment. Previously, we established a survivin promoter-regulated oncolytic adenovirus that has inhibitory effect on HCC growth. The human sulfatase-1 (hSulf-1) gene can suppress the growth factor signaling pathways, then inhibit the proliferation of cancer cells and enhance cellular sensitivity to radiotherapy and chemotherapy. I(131)-metuximab (I(131)-mab) is a monoclonal anti-HCC antibody that conjugated to I(131) and specifically recognizes the HAb18G/CD147 antigen on HCC cells. To integrate the oncolytic adenovirus-based gene therapy and the I(131)-mab-based radioimmunotherapy, this study combined the CArG element of early growth response-l (Egr-l) gene with the survivin promoter to construct a radiation-inducible enhanced promoter, which was used to recombine a radiation-inducible oncolytic adenovirus as hSulf-1 gene vector. When I(131)-mab was incorporated into the treatment regimen, not only could the antibody produce radioimmunotherapeutic effect, but the I(131) radiation was able to further boost adenoviral proliferation. We demonstrated that the CArG-enhanced survivin promoter markedly improved the proliferative activity of the oncolytic adenovirus in HCC cells, thereby augmenting hSulf-1 expression and inducing cancer cell apoptosis. This novel strategy that involved multiple, synergistic mechanisms, including oncolytic therapy, gene therapy and radioimmunotherapy, was demonstrated to exert an excellent anti-cancer outcome, which will be a promising approach in HCC treatment.

Detection of single tumor cell resistance with aptamer biochip.

In this study, a novel RNA aptamer biochip was developed for tumor cell capture and detection of single cell resistance. This biochip consists of a polydimethylsiloxane (PDMS) cover containing a channel for introducing cells and sustaining their activity and microelectrode matrix on a silicon dioxide layer. Epidermal growth factor receptor (EGFR) aptamers which specifically identify and isolate tumor cells were attached in the gap between two electrodes. After cell biochip incubation, surplus tumor cells were removed, and those dwelling on the intervals were further analyzed. When resistance measurement was completed, these cells were flushed away via controlled flow acceleration, and were collected for further analysis. The results demonstrate the convenience and efficiency of using anti-EGFR aptamer biochips for the detection of single cell resistance. This novel aptamer biochip may be used for the isolation of circulating tumor cells from peripheral blood and cell counting, or be assembled with other lab-on-a-chip components for follow-up gene and protein analysis.

Mucin production and mucous cell metaplasia in otitis media.

Otitis media (OM) with mucoid effusion, characterized by mucous cell metaplasia/hyperplasia in the middle ear cleft and thick fluid accumulation in the middle ear cavity, is a subtype of OM which frequently leads to chronic OM in young children. Multiple factors are involved in the developmental process of OM with mucoid effusion, especially disorders of mucin production resulting from middle ear bacterial infection and Eustachian tube dysfunction. In this review, we will focus on several aspects of this disorder by analyzing the cellular and molecular events such as mucin production and mucous cell differentiation in the middle ear mucosa with OM. In addition, infectious agents, mucin production triggers, and relevant signaling pathways will be discussed.

[Characteristics of the air-conducted ocular evoked myogenic potential in the young normal Chinese subjects].

OBJECTIVE: To identify the characteristics of the air-conducted ocular vestibular-evoked myogenic potential (oVEMP) in the young normal Chinese subjects. METHODS: Twenty five normal subjects were recruited for conventional examinations of oVEMP. The subjects were 19 - 45 years of age [(24.3 ± 5.6) years], 12 males and 13 females. 500 Hz air-conducted tone burst was employed for examination. The threshold of oVEMP in each ear was examined; patterns of these waves were observed and the normal ranges of the oVEMP waves responded to 100 dBnHL were calculated. RESULTS: All subjects were elicited with normal oVEMP N1-P1 waves in both ears. The response rate in these subjects was 100%. The threshold of oVEMP examination was (86.6 ± 3.6) dBnHL (x(-) ± s), latency N1 (10.1 ± 0.4) ms, latency P1 (14.7 ± 1.2) ms, interval N1-P1 (4.5 ± 1.0) ms, amplitude (7.9 ± 4.4) µV. CONCLUSIONS: Air-conducted oVEMP is a kind of vestibular-ocular reflex respond to intensive sound generated by otolithic vestibular end organs. It is stable in the young normal subjects with minor variabilities.

[Colonic sac duct for first-stage repair of colon anastomotic leakage in miniature pigs].

OBJECTIVE: To study the efficacy, safety and reliability of colonic sac duct for first-stage repair of colorectal anastomotic leakage. METHODS: An animal model of colon anastomotic leakage was established in 30 Tibet miniature pigs, which were randomly divided into treatment group and control group (n=15). Colon anastomotic leakage in the treatment group was repaired using the colonic sac duct, while the control group received conventional surgical repair. At 7, 14, and 21 days after the surgery, the healing of the anastomotic leakage was evaluated by examining the bursting pressure, tissue microvessel density and hydroxyproline content at the anastomosis. RESULTS: Using the colonic sac duct, the anastomotic leakage was successfully repaired without death of the pigs or the occurrence of intestinal stenosis or necrosis. At 7 and 14 days after the surgery, the bursting pressure, hydroxyproline contents, and microvessel density in the treatment groups were higher than those in the control group, but such difference was not found at 21 days. CONCLUSION: Colonic sac duct allows effective repair of colon anastomotic leakage, and is especially useful for leakage lasting for 48-72 h complicated by severe abdominal infection.

Identification of Id1 in acquired middle ear cholesteatoma.

OBJECTIVES: To determine (1) the relationship between chronic inflammatory changes in the ossicular chain area (OCA) and the formation of cholesteatoma and (2) the correlates between aberrant gene expression and abnormal proliferation of cholesteatoma. METHODS: Two hundred sixty-four ears with chronic otitis media that had undergone ear surgery were included in this study for statistical analysis of the relationship between abnormalities in the OCA and cholesteatoma. Fourteen middle ear cholesteatoma specimens were collected for immunohistochemical analysis of candidate molecules involved in the abnormal proliferation of keratinocytes. A cell model was used for verification of candidate molecule involvement. RESULTS: The formation of cholesteatoma was accompanied by chronic inflammatory changes in the OCA, including granulated tissue, adhesion, and stagnating effusion. The inhibitor of the DNA-binding (Id1) gene, which is involved in controlling cell cycle progression, was abundantly expressed in cholesteatoma epithelium. In vitro studies indicate that Id1 regulated the expression of nuclear factor kappaB, cyclin D1, proliferating cell nuclear antigen, and cell cycle progression of keratinocytes, CONCLUSIONS: Chronic inflammation in the OCA is closely related to the formation of cholesteatoma. The Id1/nuclear factor kappaB/cyclin D1/proliferating cell nuclear antigen signaling pathway is involved in the abnormal proliferation of keratinocytes in acquired cholesteatoma.

[Theory of local inflammatory infiltration and irritation in the pathogenesis of acquired cholesteatoma].

OBJECTIVE: To explore the deep pathogenesis of acquired cholesteatoma. METHODS: The temporal bone slides of 12 ears with retraction pocket were histopathologically studied under microscope, especially focusing on the location of retraction pocket and inflammatory pathology in the local middle ear cavity next to retraction pockets. The temporal bone slides of 11 ears with acquired cholesteatoma were histopathologically observed and 33 cases diagnosed as acquired cholesteatoma were clinically observed observed in the local middle ear cavity next to the part without retraction pocket of eardrum. The results of pathological observation of the temporal bone slides with acquired cholesteatoma and clinical observation during operation for acquired cholesteatoma show that cholesteatoma invade mainly and occupied the ossicular chain eara of the middle ear cleft. CONCLUSION: In the pathological process of otitis media, the intractable pathological changes in the ossicular chain area can inward adhere posterosuperior quadrant or pars flaccida of the eardrum to form retraction pocket and permanently infiltrate the external squamous epithelial layer of retraction pocket to excessively proliferate and keratinize, leading to formation of acquired cholesteatoma.

[Study on the phenomenon of regionally pathological difference of otitis media and its clinical significance].

OBJECTIVE: To study the feature and difference of severity of pathological changes in different areas of the middle ear cleft with otitis media (OM) and its pathogenesis and clinical significance. METHODS: The temporal bone slides of 290 ears with OM with inflammatory effusion had been studied histopathologically under microscope. The histopathological change in different areas has been comparatively observed. 256 cases with various forms of chronic otitis media (COM) have been studied with high-resolution CT, and 189 cases with COM were observed during operation, stressing on the difference of pathogical changes in different areas. RESULTS: In the process of OM, the mucosa of the eustachian tube almost has no inflammatory pathological changes, and in hemi-anterior and infer-posterior mesotympanum area was much lightly and reversible pathological change. But the pathological changes in the ossicular chain area was much more serious than the other two areas, and was irreversible or intractable such as granulation tissue, cholesteatoma etc. CONCLUSIONS: Because of the historical and anatomical distinction difference between anterior and posterior area of the middle ear cleft and blockage of internal ventilation/draining system in process of OM, the stagnancy of inflammatory effusion and formation of granulation tissue in posterior area are the main cause leading to the phenomenon of regionally pathological difference in different areas of the middle ear clefts.