Ribosomal protein L24 mediates mammalian microRNA processing in an evolutionarily conserved manner.

To investigate the mechanism(s) underlying the expression of primate-specific microRNAs (miRs), we sought DNA regulatory elements and proteins mediating expression of the primate-specific hsa-miR-608 (miR-608), which is located in the SEMA4G gene and facilitates the cholinergic blockade of inflammation by targeting acetylcholinesterase mRNA. 'Humanized' mice carrying pre-miR-608 flanked by 250 bases of endogenous sequences inserted into the murine Sema4g gene successfully expressed miR-608. Moreover, by flanking miR-608 by shortened fragments of its human genome region we identified an active independent promoter within the 150 nucleotides 5' to pre-miR-608, which elevated mature miR-608 levels by 100-fold in transfected mouse- and human-originated cells. This highlighted a regulatory role of the 5' flank as enabling miR-608 expression. Moreover, pull-down of the 150-base 5' sequence revealed its interaction with ribosomal protein L24 (RPL24), implicating an additional mechanism controlling miR-608 levels. Furthermore, RPL24 knockdown altered the expression of multiple miRs, and RPL24 immunoprecipitation indicated that up- or down-regulation of the mature miRs depended on whether their precursors bind RPL24 directly. Finally, further tests showed that RPL24 interacts directly with DDX5, a component of the large microprocessor complex, to inhibit miR processing. Our findings reveal that RPL24, which has previously been shown to play a role in miR processing in Arabidopsis thaliana, has a similar evolutionarily conserved function in miR biogenesis in mammals. We thus characterize a novel extra-ribosomal role of RPL24 in primate miR regulation.

MiR-608 Exerts Anti-inflammatory Effects by Targeting ELANE in Monocytes.

miR-608 has been indicated to play an important role in the pathogenesis of various inflammation-related diseases, including sepsis and several types of cancers. However, there is little information about the underlying mechanism, especially in inflammatory cells. In this study, an hsa-miR-608-inhibition cell model was constructed in U937 cells using a lentivirus, and gene expression profiles were determined by a cDNA microarray. Altogether, 682 genes showed a difference greater than 1.2-fold, including 184 genes downregulated and 498 genes upregulated. Among these genes, one potential miR-608-target gene, ELANE, was further investigated. A positive relationship between the expression of miR-608 and that of ELANE was found both in vivo and in vitro. In addition, decreased expression of miR-608 resulted in overexpression of ELANE at both the mRNA and protein levels. Cotransfection of HEK293T cells with a miR-608 mimic inhibited reporter activity, and mutation of the miRNA seed sequences abolished the repression of reporter activity. These results suggest that miR-608 is an important posttranscriptional regulator of ELANE expression in human monocytes and may play an important role in the process of inflammation. miR-608 and neutrophil elastase may be novel targets for the diagnosis or treatment of sepsis.

RETRACTED: Long non-coding RNA LINC00052 regulates miR-608/EGFR axis to promote progression of head and neck squamous cell carcinoma.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the corresponding author and the Editor-in-chief The corresponding author claims that the authors confused multiple pictures in different groups, resulting in overlapping figures among different groups. Fig. 7B has partial overlap with Fig. 7D of a paper authored by a different research group (Y. Gao, et al., LINC00311 promotes cancer stem-like properties by targeting miR-330-5p/TLR4 pathway in human papillary thyroid cancer, Cancer Med. 9 (2019) 1515-1528, https://doi.org/10.1002/cam4.2815). The author claimed that they had sent the pathological sections to a shared platform and that the platform mistakenly sent back pathological results from other institutions which were then used in the manuscript. The Editor-in-Chief has lost the trust in the data and the conclusion, and decided to retract the paper.

CCN3 Facilitates Runx2 and Osterix Expression by Inhibiting miR-608 through PI3K/Akt Signaling in Osteoblasts.

CCN3, otherwise known as the nephroblastoma overexpressed (NOV) protein, is a cysteine-rich protein that belongs to the CCN family and regulates several cellular functions. Osteoblasts are major bone-forming cells that undergo proliferation, mineralization, renewal, and repair during the bone formation process. We have previously reported that CCN3 increases bone morphogenetic protein 4 (BMP-4) production and bone mineralization in osteoblasts, although the role of CCN3 remains unclear with regard to osteogenic transcription factors (runt-related transcription factor 2 (Runx2) and osterix). Here, we used alizarin red-S and alkaline phosphatase staining to show that CCN3 enhances osteoblast differentiation. Stimulation of osteoblasts with CCN3 increases expression of osteogenic factors such as BMPs, Runx2, and osterix. Moreover, we found that the inhibition of miR-608 expression is involved in the effects of CCN3 and that incubation of osteoblasts with CCN3 promotes focal adhesion kinase (FAK) and Akt phosphorylation. Our results indicate that CCN3 promotes the expression of Runx2 and osterix in osteoblasts by inhibiting miR-608 expression via the FAK and Akt signaling pathways.

The miR-608 rs4919510 polymorphism may modify cancer susceptibility based on type.

Previous meta-analysis has not shown different effects of miR-608 rs4919510 polymorphism in specific cancer types and reported no significant association between rs4919510 and cancer risk among Chinese. However, more recent findings have been inconsistent. Therefore, we performed an updated meta-analysis to examine whether this polymorphism is associated with cancer risk based on ethnicity and type. A total of 18 case-control studies, comprising 12,517 cases and 15,624 controls, were included in our study. Surprisingly, in contrast with previous meta-analysis, a significant association between the rs4919510 polymorphism and cancer risk was observed in Chinese (CG vs CC: odds ratio = 1.11; 95% confidence interval = 1.04-1.19). In further stratified analyses based on cancer type, rs4919510 was significantly associated with an increased risk of papillary thyroid cancer (CG vs CC: odds ratio = 1.25; 95% confidence interval = 1.01-1.54) and exhibited borderline significant associations with increased risk of gastric cancer (GG vs CC: odds ratio = 1.27; 95% confidence interval = 1.00-1.62) and lung cancer (CG vs CC: odds ratio = 1.14; 95% confidence interval = 0.99-1.32), but a decreased risk of colorectal cancer (GG vs CC: odds ratio = 0.74; 95% confidence interval = 0.60-0.91). Moreover, the RegulomeDB database indicated that rs4919510 may affect the expression of two nearby genes ( SEMA4G and MRPL43), and the Cancer Genome Atlas database revealed that the expression level of SEMA4G was significantly lower in colorectal cancer and lung cancer tissues than that in adjacent non-tumour tissues, while the expression level of SEMA4G was significantly higher in gastric cancer tissues than that in adjacent non-tumour tissues. These findings provide evidence that the miR-608 rs4919510 polymorphism may modify cancer susceptibility in a type-specific manner. Furthermore, SEMA4G may function as an oncogene or tumour suppressor to regulate tumour development in a type-specific manner. Further studies with experimental evaluations are warranted.

MicroRNA library screening identifies growth-suppressive microRNAs that regulate genes involved in cell cycle progression and apoptosis.

Micro(mi)RNAs play important and varied roles in tumorigenesis; however, the full repertoire of miRNAs that affect cancer cell growth is not known. In this study, an miRNA library was screened to identify those that affect the growth of A549 tumor cells. Among 300 miRNAs, miR-28-5p, -323-5p, -510-5p, -552-3p, and -608 were the most effective in inhibiting cell growth. More specifically, overexpressing miR-28-5p, -323-5p, and -510-5p induced G1 arrest, as determined by flow cytometry, whereas that of miR-608 induced cell death in a caspase-dependent manner. Moreover, several genes involved in apoptosis and cell cycle progression were downregulated upon overexpression of each of the five miRNAs, with the functional targets of miR-552-3p and miR-608 confirmed by microarray, quantitative real-time PCR, and luciferase reporter assay. In miR-608-transfected cells, B cell lymphoma 2-like 1 (BCL2L1), D-type cyclin 1 (CCND1), CCND3, cytochrome b5 reductase 3 (CYB5R3), phosphoinositide 3-kinase regulatory subunit 2 (PIK3R2), specificity protein 1 (SP1), and phosphorylated Akt were all downregulated, while Bcl-2-interacting killer (BIK) was upregulated. Moreover, miR-608 was determined to have a suppressive function on tumor growth in an NCI-H460 xenograft model. These findings provide insights into the roles of five miRNAs in growth inhibition and their potential function as cancer therapeutics.

Hsa-circ-0052001 promotes gastric cancer cell proliferation and invasion via the MAPK pathway.

BACKGROUND: Gastric cancer (GC) ranks fourth among the causes of death from malignant tumors in the world. Studies have implicated the dysregulation of circRNAs with GC. However, the relationship between hsa-circ-0052001 and GC is unclear. METHODS: In our current study, we assessed the expression levels of hsa-circ-0052001 in GC cells and tissues using quantitative real-time PCR (qPCR). The role of hsa-circ-0052001 expression on the proliferation and invasion of GC cells was assessed using in vitro experiments. The role of hsa-circ-0052001 on the proliferation of GC cells was also analyzed using in vivo models. The pathways downstream of hsa-circ-0052001 were identified using bioinformatics analyses, western blot (WB) assays, and qRT-PCR. RESULTS: We found that compared with normal gastric mucosa epithelial cells and adjacent paracancer tissues, hsa-circ-0052001 was overexpressed in GC cells and tissues. Also, the hsa-circ-0052001 level was linked to patient clinicopathological characteristics of GC. Cell proliferation and metastatic ability were inhibited in gastric cancer cells when hsa-circ-0052001 was knocked down in vitro and cancer growth in vivo. Mechanistically, hsa-circ-0052001 promoted the carcinogenesis of GC cells via the MAPK signal pathway. CONCLUSION: Hsa-circ-0052001 functions as a tumor gene in promoting the progression of GC through MAPK pathway, which has provided a promising target for patients with GC.

Biological Functions and Molecular Mechanisms of MiR-608 in Cancer.

In recent years, microRNAs (miRNAs) have attracted much attention because of their prominent role in cancer. An increasing number of studies have shown that miRNAs play an important role in a variety of tumors. miR-608 has been reported to be decreased in cancers, especially in solid tumors. miR-608 is regarded as a tumor suppressor, which has been verified through a large number of experiments both in vivo and in vitro. miR-608 participates in many biological processes, including cell proliferation, invasion, migration, and apoptosis, by inhibiting transmembrane proteins and many signaling pathways. Here, we summarize the expression profile and biological functions and mechanism of miR-608, suggesting that miR-608 is an ideal diagnostic and prognostic biomarker and a treatment target for cancer.

Long Non-Coding RNA LINC02747 Promotes the Proliferation of Clear Cell Renal Cell Carcinoma by Inhibiting miR-608 and Activating TFE3.

With the rapid development of biotechnology, long noncoding RNAs (lncRNAs) have exhibited good application prospects in the treatment of cancer, and they may become new treatment targets for cancer. This study aimed to explore lncRNAs in clear cell renal cell carcinoma (ccRCC). Differentially expressed lncRNAs in 54 pairs of ccRCC tissues and para-carcinoma tissues were analyzed in The Cancer Genome Atlas (TCGA), and the most significant lncRNAs were selected and verified in ccRCC tissues. We found that lncRNA LINC02747 was highly expressed in ccRCC (P < 0.001) and was closely related to high TNM stage (P = 0.006) and histological grade (P = 0.004) and poor prognosis of patients (P < 0.001). In vivo and in vitro experiments confirmed that LINC02747 could promote the proliferation of ccRCC cells. We also found that LINC02747 regulated the proliferation of RCC cells by adsorbing miR-608. Subsequent mechanistic research showed that miR-608 is downregulated in ccRCC (P < 0.001), and overexpression of miR-608 inbibited the proliferation of RCC cells. Moreover, we found that TFE3 is a direct target gene of miR-608. MiR-608 regulated the proliferation of RCC cells by inhibiting TFE3. In conclusion, LINC02747 upregulates the expression of TFE3 by adsorbing miR-608, ultimately promoting the proliferation of ccRCC cells. The above findings indicate that LINC02747 acts as an oncogene in ccRCC and may be developed as a molecular marker for the diagnosis and prognosis of ccRCC. The LINC02747/miR-608/TFE3 pathway may become a new therapeutic target for ccRCC.

LINC00963 facilitates acute myeloid leukemia development by modulating miR-608/MMP-15.

Despite continuous improvements of AML therapy, the prognosis of AML patients remains unsatisfactory. Recently, lncRNAs have been reported to participate in the development of AML. Our data demonstrated that MMP15 and LINC00963 were upregulated and miR-608 was decreased in AML cells (THP-1, HL-60, HEL and MOLM-13) compared to HS-5 cells. RT-qPCR results showed that LINC00963 levels were higher in the serum and bone marrow of AML cases than in controls. Moreover, overexpression of LINC00963 promoted AML cell growth and EMT progression in both THP-1 and HL-60 cells. Furthermore, miR-608 levels were downregulated in the serum and bone marrow of AML cases compared with controls, and Pearson's correlation analysis indicated that LINC00963 was negatively correlated with miR-608 in the serum and bone marrow of AML samples. In addition, we demonstrated that LINC00963 sponged miR-608 expression and that MMP-15 was a target of miR-608 in AML cells. Finally, rescue experiments indicated that ectopic expression of LINC00963 accelerated cell growth and EMT development by modulating MMP-15. These data demonstrated that LINC00963 acted as an oncogene and may be a potential target for AML treatment.

Toosendanin Suppresses Glioma Progression Property and Induces Apoptosis by Regulating miR-608/Notch Axis.

BACKGROUND: Glioma is one the most common and aggressive primary tumors of adult central nervous system worldwide, which tends to develop dysplasia and metastasis. Recently, toosendanin (TSN) has shown pharmacological effects in several cancers. However, little is known about the underlying mechanism of the effect of TSN on glioma and its relationship between miRNA in glioma. METHODS: Cell proliferation, cell cycle, cell apoptosis and cell migration were analyzed by CCK-8 cell viability, flow cytometry, wound scratch healing, transwell and Western blotting assays, respectively, in vitro. The regulation relationships between TSN and miR-608 or between miR-608 and Notch1 (Notch2) were examined using qRT-PCR, dual-luciferase and Western blotting assays. The functional effects of TSN through regulating miR-608 and Notch1 (Notch2) were further examined using a xenograft tumor mouse model in vivo. RESULTS: After TSN concentration was increased from 50 nM, 100 nM to 150 nM, cell proliferation and cell cycle were gradually reduced, and the cell apoptosis rate was increased in U-138MG or U-251MG cells. Wound-healing and transwell assays results showed that cell migration was significantly inhibited in TSN treatment cells (TSN treatment, 50 nM) compared to control cells. Mechanistic studies revealed that TSN up-regulated the expression of microRNA-608 (miR-608), while down-regulated the expression of miR-608's target, Notch1 and Notch2. Over-expression of Notch1 and Notch2 partly attenuated TSN-induced tumor suppressive function. Moreover, in vivo experiments revealed that TSN treatment led to a significant inhibition of tumor growth, suggesting that it might be a promising drug for the treatment of glioma. CONCLUSION: In the present study, a novel established functional manner of TSN/miR-608/Notch1 (Notch2) axis was systematically indicated, which might provide prospective intervention ways for glioma therapy.

Long non-coding RNA BLACAT1 expedites osteosarcoma cell proliferation, migration and invasion via up-regulating SOX12 through miR-608.

BACKGROUND: Osteosarcoma is the most common type of bone malignancy. Increasing evidence indicated that long non-coding RNAs (lncRNAs) possess multiple functions in the development of cancer and can be used as indicators of prognosis and diagnosis. LncRNA BLACAT1 has been found to promote the proliferation of breast cancer cells. However, the role of BLACAT1 in osteosarcoma remains largely unknown. METHODS: QRT-PCR analysis was employed to evaluate mRNA expressions. Western blot was performed to measure relevant protein level. Colony formation and EdU assays were conducted to certify proliferative ability. TUNEL assay was finalized to assess apoptotic cells. Wound-healing and transwell assays were utilized for the exploration of migrating and invasive abilities. The subcellular distribution of BLACAT1 was studied by nucleus-cytoplasm separation assay. Relevant mechanical experiments were combined to elucidate molecular relationship between molecules. RESULTS: BLACAT1 was highly expressed in osteosarcoma. BLACAT1 promoted the proliferation and migration of osteosarcoma cells. BLACAT1 acted as a sponge for miR-608 to augment the expression of Sex determining region Y-box protein 12 (SOX12), the direct target of miR-608. Further, inhibiting miR-608 recovered the repressive effect of silenced BLACAT1 on the malignant behaviors of osteosarcoma cells. CONCLUSION: This study highlighted the contribution of BLACAT1/miR-608/SOX12 axis to the progression of osteosarcoma, suggesting novel targets for osteosarcoma therapy.

The long noncoding RNA NORAD promotes the growth of gastric cancer cells by sponging miR-608.

Dysfunction of long non-coding RNAs (lncRNAs) has been suggested to play pivotal roles in the initiation and progression of human cancers. The noncoding RNA activated by DNA damage (NORAD) is a recently identified, highly conserved lncRNA that is essential for the mitotic cell division. Recent studies demonstrated the potential oncogenic function of NORAD in bladder cancer and colon cancer, however, the role and clinical value of NORAD have not been illustrated in gastric cancer. Here, we found that NORAD was highly expressed in gastric cancer tissues and cell lines. Overexpression of NORAD was significantly correlated with the worse prognosis of the gastric cancer patients. Down-regulation of NORAD suppressed the proliferation and migration of gastric cancer cells. Mechanistically, NORAD acted as a competitive endogenous RNA (ceRNA), which sponged miR-608 and suppressed the expression of miR-608 in gastric cancer cells. Further experiments demonstrated that miR-608 targeted the forkhead box O6 (FOXO6) and negatively regulated the expression of FOXO6. Consistent with the inhibitory effect of NORAD on miR-608, overexpression of NORAD enhanced the level of FOXO6 in gastric cancer cells. Overexpression of FOXO6 attenuated the inhibitory effect of miR-608 on the gastric cancer cell growth. Collectively, our results demonstrated that NORAD promoted the growth of gastric cancer cells via modulating the miR-608/FOXO6 pathway.

Involvement of NORAD/miR-608/STAT3 axis in carcinostasis effects of physcion 8-O-ß-glucopyranoside on ovarian cancer cells.

We planned to dig the carcinostasis activity of physcion 8-O-ß-glucopyranoside (PG) in ovarian cancer cells and explored whether long non-coding RNA NORAD was the potential cause of the carcinostasis impact of PG. The impacts of PG on the tumour cell behaviours (including cell viability, apoptosis, migration and invasion) of SKOV3 cells were grabbed. The levels of NORAD in cancer tissues and cell lines were determined; afterwards, the impacts of abnormal expression of NORAD on the tumour cell behaviours of SKOV3 cells were assessed. Moreover, we explored whether NORAD modulated the level of STAT3 by competitively sponging miR-608, thus mediating the antineoplastic effects of PG on ovarian cancer cells. PG suppressed cell viability, enhanced apoptosis and lessened migration and invasion of SKOV3 cells. NORAD was upregulated in ovarian cancer tissues and cells. Silencing of NORAD lessened cell viability, migration and invasion, but induced apoptosis of SKOV3 cells, whereas overexpression of NORAD had opposite effects. Moreover, PG decreased the expression of NORAD. Overexpression of NORAD reversed the effects of PG treatment on the cell biological performances of SKOV3 cells, which were further reversed after overexpression of miR-608 simultaneously. Furthermore, STAT3 was tested as a target gene of miR-608, and the impact of NORAD in PG-treated SKOV3 cells were through the miR-608-mediated STAT3. Our findings reveal that NORAD/miR-608/STAT3 axis is pivotal in mediating the antineoplastic impacts of PG on ovarian cancer cells, which may offer a novel explanation in the therapy of ovarian cancer.

Expression of miR-490-5p, miR-148a-3p and miR-608 in bladder cancer and their effects on the biological characteristics of bladder cancer cells.

Changes in the expression of miR-490-5p, miR-148a-3p and miR-608 in bladder cancer tissues were studied. A total of 30 patients with bladder cancer who had surgical resection in the Hunan Provincial People's Hospital (Changsha, China) from April 2015 to August 2016 were selected. RT-qPCR was used to detect the expression levels of miR-490-5p, miR-148a-3p and miR-608. The expression vectors of miR-490-5p, miR-148a-3p and miR-608 were respectively transfected and divided into three groups: blank cell group, gene transfection group (groups A-C) and negative transfection group (NC group). CCK8 was used to detect cell proliferation and flow cytometry was used to detect the condition of apoptosis of each group, and the Transwell chamber was used to detect the invasion ability of the cells. After the transfection, the expression level of miR-490-5p in group A was significantly higher than that in the NC and blank groups, and the expression level of miR-148a-3p in group B was significantly higher than that in the NC and blank groups. The expression level of miR-608 in group C was significantly higher than that in the NC and blank groups (P<0.001). The survival rates of the cells in groups A-C were significantly lower than those in the NC and blank groups at 48 and 72 h (P<0.001). After the transfection, the number of invasive cells and the apoptosis rates in groups A-C were significantly higher than those in the NC and blank groups (P<0.05). miR-490-5p, miR-148a-3p and miR-608 promoted proliferation of bladder cancer T24 cells and inhibited apoptosis of the cells and showed potential to become a new target for the future treatment of bladder cancer.

HOXD-AS1 promotes cell proliferation, migration and invasion through miR-608/FZD4 axis in ovarian cancer.

Evidence is accumulating that long non-coding RNAs (lncRNAs) exert crucial roles in the incidence and progression of tumors. HOXD cluster antisense RNA 1 (HOXD-AS1), a cancer-related lncRNA, has been frequently reported to be involved in tumorigenesis and dysregulated in multiple types of human cancers; however, little is known about its role in ovarian cancer (OC). This study aimed to explore the role of HOXD-AS1 in OC and elucidate the potential mechanism involved. In the current study, HOXD-AS1 was observed to be upregulated in both OC tissues and cell lines. Besides, elevated expression of HOXD-AS1 was found to be associated with poor prognosis of OC patients. Furthermore, functional studies demonstrated that HOXD-AS1 promoted OC cell proliferation and colony formation, and enhanced the migration and invasion capabilities of OC cells. Mechanistically, HOXD-AS1 was detected to positively regulate the expression of frizzled family receptor 4 (FZD4) by competitively binding to miR-608. Taken together, HOXD4-AS1 exerts tumor-promoting functions through miR-608/FZD4 axis in OC. Our findings indicate that HOXD-AS1 may be used as a promising therapeutic target and a novel prognostic biomarker for OC.

Investigating the Association Between miR-608 rs4919510 and miR-149 rs2292832 with Colorectal Cancer in Iranian Population.

BACKGROUND: Single Nucleotide Polymorphisms (SNPs) in microRNA (miRNA) networks may serve as diagnostic and prognostic biomarkers of a variety of diseases such as cancer. Some studies have been performed to examine associations between miR-149 and miR-608 polymorphisms and susceptibility to colorectal cancer, but the results remain controversial and race-dependent. OBJECTIVE: The aim of our study was to investigate the association of miR-608 (rs4919510) and miR- 149 (rs2292832) with colorectal cancer and its clinical features in a sample of Iranian population. METHODS: This retrospective study was conducted on 76 CRC cases and 70 controls. Genotyping was performed using the polymerase chain reaction-restriction fragment length polymorphism (PCRRFLP) method. To confirm the RFLP process, 10% of the PCR products were validated by direct sequencing. RESULTS: Our findings showed significant correlation between adjusted data of rs2292832 with sex and age in TT genotype (OR= 5.148, 95% CI=1.081 ± 24.511, P=0.04). Distribution of rs4919510 polymorphism was not significantly different between controls and patients (CG, adjusted OR= 1.243, 95% CI=0.546 ± 2.831; P=0.604 and GG, adjusted OR= 0.249, 95% CI=0.063 ± 0.959; P=0.05). On the other hand, our results showed that a significant correlation was present between metastatic clinicopathological features and miR-608 (rs4919510) polymorphism (P=0.044). CONCLUSION: Our findings reveal that genotypes of rs2292832 and rs4919510 are not associated with risk of colorectal cancer in Iranian population. Moreover, the CC genotype of rs4919510 contributes to the metastatic features of the colorectal cancer.

Association of miR-608 rs4919510 polymorphism and cancer risk: a meta-analysis based on 13,664 subjects.

Single nucleotide polymorphisms (SNPs) in MicroRNAs (miRNAs) are involved in the mechanism of carcinogenesis. Several studies have evaluated the association of rs4919510 SNP in miR-608 with cancer susceptibility in different types of cancer, with inconclusive outcomes. To obtain a more precise estimation, we carried out this meta-analysis through systematic retrieval from the PubMed and Embase database. A total of 10 case-control studies were analyzed with 6,000 cases and 7,664 controls. The results showed that 4919510 SNP in miR-608 was significantly associated with decreased cancer risk only in recessive model (CC vs. GG+GC: OR=0.89, 95% CI: 0.82-0.97, P=0.009). By further stratified analysis, we found that rs4919510 SNP had some relationship with decreased cancer risk in both homozygote model (CC vs. GG: OR=0.59, 95% CI: 0.36-0.96, P=0.034) and dominant model (CG+ CC vs. GG: OR=0.60, 95% CI: 0.37-0.98, P=0.042) in Caucasians but no relationship in any genetic model in Asians. These results indicated that miR-608 rs4919510 polymorphism may contribute to the decreased cancer susceptibility and could be a promising target to forecast cancer risk for clinical practice. However, to further confirm these results, well-designed large scale case-control studies are needed in the future.

microRNA-342-5p and miR-608 inhibit colon cancer tumorigenesis by targeting NAA10.

miRNAs have been shown to play pivotal roles in the establishment and progression of colon cancer, but their underlying mechanisms are not fully understood. N-acetyltransferase NAA10 participates in many cellular processes, including tumorigenesis. Here we showed that miR-342-5p and miR-608 suppressed the tumorigenesis of colon cancer cells in vitro and in vivo by targeting NAA10 mRNA for degradation. Overexpression of miR-342-5p or miR-608 decreased NAA10 mRNA and protein levels and thereby suppressed cell proliferation, migration, and cell-cycle progression, as well as promoted apoptosis in SW480 and SW620 cells. More importantly, miR-342-5p and miR-608 significantly decreased the tumorigenic capacity of SW480 and SW620 cells in a mouse xenograft model. We also observed an inverse correlation between the expression of NAA10 and that of both miRNAs. Our results implicate miR-342-5p and miR-608 in colon cancer development and unveil the underlying mechanism of this phenomenon, which involves NAA10.