Liquid biopsy in lung cancer: significance in diagnostics, prediction, and treatment monitoring.

Primary lung cancer is one of the most common malignant tumors in China. Approximately 60% of lung cancer patients have distant metastasis at the initial diagnosis, so it is necessary to find new tumor markers for early diagnosis and individualized treatment. Tumor markers contribute to the early diagnosis of lung cancer and play important roles in early detection and treatment, as well as in precision medicine, efficacy monitoring, and prognosis prediction. The pathological diagnosis of lung cancer in small biopsy specimens determines whether there are tumor cells in the biopsy and tumor type. Because biopsy is traumatic and the compliance of patients with multiple biopsies is poor, liquid biopsy has become a hot research direction. Liquid biopsies are advantageous because they are nontraumatic, easy to obtain, reflect the overall state of the tumor, and allow for real-time monitoring. At present, liquid biopsies mainly include circulating tumor cells, circulating tumor DNA, exosomes, microRNA, circulating RNA, tumor platelets, and tumor endothelial cells. This review introduces the research progress and clinical application prospect of liquid biopsy technology for lung cancer.

The power and the promise of circRNAs for cancer precision medicine with functional diagnostics and prognostic prediction.

Circular RNA (circRNA) is a large class of covalently closed circRNA. As a member of competitive endogenous RNA, it participates in the regulation of circRNA-miRNA-mRNA network and plays an important role in the regulation of physiology and pathology. CircRNA is produced by the reverse splicing of exon, intron or both, forming exon or intron circRNA. Studies have shown that circRNA is a ubiquitous molecule, which exceeds the linear mRNA distributed in human cells. Because of its covalent closed-loop structure, circRNA is resistant to RNase R, which is more stable than linear mRNA; circRNA is highly conserved in different species. It was found that circRNA competitively adsorbs miRNA, as a miRNA sponge, to involve in the expression regulation of a variety of genes and plays an important role in tumor development, invasion, metastasis and other processes. These molecules offer new potential opportunities for therapeutic intervention and serve as biomarkers for diagnosis. In this paper, the origin, characteristics and functions of circRNA and its role in tumor development, invasion and metastasis, diagnosis and prognosis are reviewed.

microRNA-320b suppresses HNF4G and IGF2BP2 expression to inhibit angiogenesis and tumor growth of lung cancer.

We examined the effect of microRNA-320b (miR-320b) on tumor growth and angiogenesis in lung cancer and also determined its downstream molecular mechanisms. Lung cancer tissues and adjacent non-cancerous tissues were collected from 66 patients with lung cancer. miR-320b expression was experimentally determined to be expressed at low level in cancer tissues. The results of gain-of-function experiments suggested that miR-320b overexpression suppressed cancer cell invasion, tube formation, tumor volume and angiogenesis in xenografted nude mice. Hepatocyte nuclear factor 4 gamma (HNF4G) was identified as a target of miR-320b based on in silico analysis. Dual-luciferase reporter gene assays further identified the binding relationship between HNF4G and miR-320b. Lung cancer tissues exhibited increased expression of HNF4G and insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2). Meanwhile, HNF4G knockdown suppressed IGF2BP2 expression, thereby repressing cancer cell invasion and tube formation. Furthermore, IGF2BP2 modified m6A to increase the expression of thymidine kinase 1 (TK1), thus promoting angiogenesis. In nude mice, restoration of TK1 reversed the suppressive effect of miR-320b overexpression on tumor growth rate and CD31 expression. In conclusion, miR-320b suppresses lung cancer growth and angiogenesis by inhibiting HNF4G, IGF2BP2 and TK1.

Long non-coding RNA NORAD promotes pancreatic cancer stem cell proliferation and self-renewal by blocking microRNA-202-5p-mediated ANP32E inhibition.

BACKGROUND: Cancer stem cells (CSCs) are key regulators in the processes of tumor initiation, progression, and recurrence. The mechanism that maintains their stemness remains enigmatic, although the role of several long noncoding RNAs (lncRNAs) has been highlighted in the pancreatic cancer stem cells (PCSCs). In this study, we first established that PCSCs overexpressing lncRNA NORAD, and then investigated the effects of NORAD on the maintenance of PCSC stemness. METHODS: Expression of lncRNA NORAD, miR-202-5p and ANP32E in PC tissues and cell lines was quantified after RNA isolation. Dual-luciferase reporter assay, RNA pull-down and RIP assays were performed to verify the interactions among NORAD, miR-202-5p and ANP32E. We then carried out gain- and loss-of function of miR-202-5p, ANP32E and NORAD in PANC-1 cell line, followed by measurement of the aldehyde dehydrogenase activity, cell viability, apoptosis, cell cycle distribution, colony formation, self-renewal ability and tumorigenicity of PC cells. RESULTS: LncRNA NORAD and ANP32E were upregulated in PC tissues and cells, whereas the miR-202-5p level was down-regulated. LncRNA NORAD competitively bound to miR-202-5p, and promoted the expression of the miR-202-5p target gene ANP32E thereby promoting PC cell viability, proliferation, and self-renewal ability in vitro, as well as facilitating tumorigenesis of PCSCs in vivo. CONCLUSION: Overall, lncRNA NORAD upregulates ANP32E expression by competitively binding to miR-202-5, which accelerates the proliferation and self-renewal of PCSCs.

Correction to: Proteogenomic characterization and comprehensive integrative genomic analysis of human colorectal cancer liver metastasis.

Following publication of the original article [1], the authors reported an error in affiliation 5.

miR-30 Family Reduction Maintains Self-Renewal and Promotes Tumorigenesis in NSCLC-Initiating Cells by Targeting Oncogene TM4SF1.

Increasing evidence indicates that tumor-initiating cells (TICs) are responsible for the occurrence, development, recurrence, and development of the drug resistance of cancer. MicroRNA (miRNA) plays a significant functional role by directly regulating targets of TIC-triggered non-small-cell lung cancer (NSCLC), but little is known about the function of the miR-30 family in TICs. In this study, we found the miR-30 family to be downregulated during the spheroid formation of NSCLC cells, and patients with lower miR-30a/c expression had shorter overall survival (OS) and progression-free survival (PFS). Moreover, transmembrane 4 super family member 1 (TM4SF1) was confirmed to be a direct target of miR-30a/c. Concomitant low expression of miR-30a/c and high expression of TM4SF1 correlated with a shorter median OS and PFS in NSCLC patients. miR-30a/c significantly inhibited stem-like characteristics in vitro and in vivo via suppression of its target gene TM4SF1, and then it inhibited the activity of the mTOR/AKT-signaling pathway. Thus, our data provide the first evidence that TM4SF1 is a direct target of miR-30a/c and miR-30a/c inhibits the stemness and proliferation of NSCLC cells by targeting TM4SF1, suggesting that miR-30a/c and TM4SF1 may be useful as tumor biomarkers for the diagnosis and treatment of NSCLC patients.

Proteogenomic characterization and comprehensive integrative genomic analysis of human colorectal cancer liver metastasis.

BACKGROUND: Proteogenomic characterization and integrative and comparative genomic analysis provide a functional context to annotate genomic abnormalities with prognostic value. METHODS: Here, we analyzed the proteomes and performed whole exome and transcriptome sequencing and single nucleotide polymorphism array profiling for 2 sets of triplet samples comprised of normal colorectal tissue, primary CRC tissue, and synchronous matched liver metastatic tissue. RESULTS: We identified 112 CNV-mRNA-protein correlated molecules, including up-regulated COL1A2 and BGN associated with prognosis, and four strongest hot spots (chromosomes X, 7, 16 and 1) driving global mRNA abundance variation in CRC liver metastasis. Two sites (DMRTB1R202H and PARP4V458I) were revealed to frequent mutate only in the liver metastatic cohort and displayed dysregulated protein abundance. Moreover, we confirmed that the mutated peptide number has potential prognosis value and somatic variants displayed increased protein abundance, including high MYH9 and CCT6A expression, with clinical significance. CONCLUSIONS: Our proteogenomic characterization and integrative and comparative genomic analysis provides a new paradigm for understanding human colon and rectal cancer liver metastasis. TRIAL REGISTRATION: ClinicalTrials, NCT02917707. Registered 28 September 2016, https://clinicaltrials.gov/ct2/show/NCT02917707 .

Reduced hsa-miR-124-3p levels are associated with the poor survival of patients with hepatocellular carcinoma.

Hsa-MicroRNA-124a-3p (hsa-miR-124-3p) is involved in tumor progression in certain malignant tumors. However, its function and clinical implication in hepatocellular carcinoma (HCC) have not yet been illustrated. In this study, we explored the expression and prognostic value of hsa-miR-124-3p in patients with HCC. Hsa-miR-124-3p expression in HCC was analyzed in silico, which was subsequently confirmed by quantitative PCR in 155 HCC biopsy samples. Overall survival (OS) and disease-free survival in HCC patients was evaluated by Kaplan-Meier survival analysis, and univariate and multivariate Cox proportional hazard models were used. The in silico results demonstrated that hsa-miR-124-3p was reduced in cell lines and tissues of HCC, and hsa-miR-124-3p expression was lower in HCC tumor samples than in normal liver tissues. Moreover, a decrease in hsa-miR-124-3p expression was closely correlated with tumor diameter (≥ 5 cm) and number of lesions (multiple). Lower hsa-miR-124-3p expression was shown to be correlated with a shorter OS and poor prognosis in HCC. Our findings demonstrate that hsa-miR-124-3p might be a potential target for the diagnosis and prognosis of HCC.

Up-regulated microRNA-299 corrected with poor prognosis of glioblastoma multiforme patients by targeting ELL2.

BACKGROUND: An increasing understanding of the genes and molecular pathways of glioblastoma multiforme (GBM) can provide us a useful insight for the development of more effective targeted therapeutic. METHODS: To investigate the expression and clinical significance of miR-299 and its target genes in GBM, the expression levels of miR-299 and its target gene in human normal brain tissues and GBM were analyzed in silico using genes microarray and hierarchical clustering analysis followed by validation with quantitative RT-PCR. RESULTS: Our results show that miR-299 is up-regulated in GBM patients. Moreover, patients with low miR-299 expression had longer overall survival (OS) compared with those with high miR-299 expression. RNA polymerase II elongation factor, ELL2, was identified as a miR-299 direct target. High expression of ELL2 together with miR-299 down-regulation correlated with a shorter median OS. CONCLUSIONS: Our results provide the first evidence that ELL2 is a direct target of miR-299 and increased ELL2 expression and down-regulation of miR-299 are associated with GBM progression and poor prognosis in patients, suggesting that ELL2 and miR-299 might have potential prognostic value and be used as tumor biomarkers for the diagnosis of patients with GBM.

p38 MAPK inhibition alleviates experimental acute pancreatitis in mice.

BACKGROUND: The mitogen-activated protein kinases (MAPKs) signaling pathway is involved in inflammatory process. However, the mechanism is not clear. The present study was to investigate the role of p38 MAPK in acute pancreatitis in mice. METHODS: Mice were divided into 4 groups: saline control; acute pancreatitis induced with repeated injections of cerulein; control plus p38 MAPK inhibitor SB203580; and acute pancreatitis plus SB203580. The pancreatic histology, pancreatic enzymes, cytokines, myeloperoxidase activity, p38 MAPK and heat shock protein (HSP) 60 and 70 were evaluated. RESULTS: Repeated injections of cerulein resulted in acute pancreatitis in mice, accompanying with the activation of p38 MAPK and overexpression of HSP60 and HSP70 in the pancreatic tissues. Treatment with SB203580 significantly inhibited the activation of p38 MAPK, and furthermore, inhibited the expression of HSP60 and HSP70 in the pancreas, the inflammatory cytokines in the serum, and myeloperoxidase activity in the lung. CONCLUSION: The p38 MAPK signaling pathway is involved in the regulation of inflammatory response and the expression of HSP60 and HSP70 in acute pancreatitis.

Association of glutathione S-transferase M1, T1, and P1 polymorphisms with renal cell carcinoma: evidence from 11 studies.

The glutathione S-transferases (GSTs) are a gene superfamily of phase II metabolic enzymes that has attracted a considerable attention as a candidate gene for renal cell carcinoma (RCC) based on its enzyme function as a key factor in biotransformation pathways. In the past decade, a number of case-control studies were conducted to investigate the association of GST genetic polymorphisms and RCC risk. However, studies on the association between GST (GSTM1, GSTT1, and GSTP1) polymorphisms and RCC remain to be conflicting. To derive a more precise estimation of the relationship, a meta-analysis of 2,189 cases and 3,817 controls from 11 case-control studies was performed. Overall, the summarized odds ratio for RCC of the GSTM1 null and GSTT1 null polymorphisms was 1.02 (95% confidence interval (CI) 0.91-1.15, P = 0.70) and 1.28 (95% CI 0.96-1.72, P = 0.09), respectively. No significant results were observed in heterozygous and homozygous genotypes when compared with wild-type genotype for GSTP1 I105V polymorphism. However, the GSTM1-GSTT1 interaction analysis showed that the dual null genotype of GSTM1/GSTT1 was significantly associated with an increased RCC risk (odds ratio (OR) = 1.42, 95% CI 1.14-1.76, P = 0.001). In the stratified analyses by ethnicity, significant gene-disease association was obtained among Asians for GSTT1 and GSTP1 polymorphisms. In our meta-analysis, the associations between variations of GSTs and RCC may vary in different ethnic populations, and the interaction between unfavorable GST genotypes may exist.

Differential gene expression of the key signalling pathway in para-carcinoma, carcinoma and relapse human pancreatic cancer.

Pancreatic cancer (PC) has a high rate of mortality and a poorly understood mechanism of progression. Investigation of the molecular mechanism of PC and exploration of the specific markers for early diagnosis and specific targets of therapy are key points to prevent and treat PC effectively and to improve their prognosis. In our study, expression profiles experiment of para-carcinoma, carcinoma and relapse human PC was performed using Agilent human whole genomic oligonucleotide microarrays with 45 000 probes. Differentially expressed genes related with PC were screened and analysed further by Gene Ontology term analysis and Kyoto encyclopaedia of genes and genomes pathway analysis. Our results showed that there were 3853 differentially expressed genes associated with pancreatic carcinogenesis and relapse. In addition, our study found that PC was related to the Jak-STAT signalling pathway, PPAR signalling pathway and Calcium signalling pathway, indicating their potential roles in pancreatic carcinogenesis and progress.

Artificial intelligence for disease diagnostics still has a long way to go.

Artificial intelligence (AI) can sometimes resolve difficulties that other advanced technologies and humans cannot. In medical diagnostics, AI has the advantage of processing figure recognition, especially for images with similar characteristics that are difficult to distinguish with the naked eye. However, the mechanisms of this advanced technique should be well-addressed to elucidate clinical issues. In this letter, regarding an original study presented by Takayama et al, we suggest that the authors should effectively illustrate the mechanism and detailed procedure that artificial intelligence techniques processing the acquired images, including the recognition of non-obvious difference between the normal parts and pathological ones, which were impossible to be distinguished by naked eyes, such as the basic constitutional elements of pixels and grayscale, special molecules or even some metal ions which involved into the diseases occurrence.

RLIP76 is overexpressed in human glioblastomas and is required for proliferation, tumorigenesis and suppression of apoptosis.

The guanosine triphosphatase-activating protein RLIP76 is overexpressed in many malignant tumor cells, but it is unclear if RLIP76 overexpression contributes to the high proliferative potential of glioma cells. We demonstrate that RLIP76 messenger RNA and protein expression are positively correlated with glioma grade and that higher RLIP76 expression correlates with shorter patient survival. Immunohistochemical staining revealed that RLIP76 expression was positively correlated with the expression of Ki-67, a biomarker for cell proliferation. Inhibition of RLIP76 expression in U87 and U251 glioma cell lines by stable transfection of a targeted siRNA suppressed anchorage-independent growth and enhanced apoptosis in vitro. Conversely, overexpression of RLIP76 in SW1088 and U251 cell lines enhanced proliferation and reduced apoptosis. Inhibition of RLIP76 in U251 cells also significantly suppressed tumorigenicity and induced apoptosis in an endotopic xenograft mouse model. Moreover, we demonstrate that knockdown of RLIP76 increases apoptosis in different human gliomas independently of p53 status. In addition, a constitutively active Rac1 reversed both the suppression of proliferation and the promotion of apoptosis induced by the RLIP76-targeted siRNA, indicating that RLIP76 is an upstream activator of Rac1. Rac1-mediated suppression of apoptosis and promotion of proliferation were dependent on intact c-jun N-terminal kinase (JNK) signaling. Furthermore, we demonstrate that RLIP76 promotes proliferation and suppresses glioma cell apoptosis through a mechanism independent of Rho-selective GTPase-activating protein. Instead, we found that the adenosine triphosphatase function of Rlip76 modulates Rac1 activity by regulating Rac1 protein ubiquitylation and degradation. These data demonstrate that RLIP76 may suppress apoptosis and promote the proliferation of glioma cells by direct adenosine triphosphate-dependent xenobiotic transport and by activating the Rac1-JNK signaling pathway. Inhibition of RLIP76 signaling is a potential treatment for malignant glioma.

A single-center randomized controlled trial of local methylcobalamin injection for subacute herpetic neuralgia.

OBJECTIVE: This study explored the efficacy of local methylcobalamin injection in relieving pain and improving the quality of life among subjects with subacute herpetic neuralgia. DESIGN: A single-center, randomized controlled trial of local methylcobalamin injection was performed. SUBJECTS: Ninety-eight subjects (age, ≥ 50 years) with unilateral, dermatomal pain ≥ 4 related to herpes zoster on the torso lasting for 30 days after onset of rash were enrolled. METHODS: Subjects were randomized to receive local methylcobalamin injection (N = 33), oral methylcobalamin (N = 33), or subcutaneous 1.0% lidocaine injection (N = 32) for 4 weeks. Worst pain severity, global impression of change, continuous spontaneous pain, paroxysmal pain, allodynia, paresthesia, interference with activities of daily living, and quality of life were assessed after 28-day treatment period. RESULTS: Time per group interaction and group difference on overall pain at each follow-up point were statistically significant (P < 0.001) among groups. In the injected methylcobalamin group, the overall pain (P < 0.001), continuous spontaneous pain (P < 0.05), paroxysmal pain (P < 0.05), and allodynia (P < 0.05) revealed a significant effect at each follow-up point as compared with the other groups. Twenty subjects achieved pain reduction ≥ 50%, 24 perceived worst pain ≤ 3, 24 stopped using analgesics at end point; activities of daily living and quality of life improved significantly as compared with the other groups (P < 0.001). Although both of the other groups showed a significant response after the 14-day treatment (P < 0.001) compared with the baseline, oral methylcobalamin did not provide any significantly pain relief (P > 0.05). CONCLUSIONS: Local methylcobalamin injection was not only efficacious in relieving pain, but also appears to be tolerable and a potential choice of treatment for subacute herpetic neuralgia.

Identification and validation of functional roles for three MYC-associated genes in hepatocellular carcinoma.

BACKGROUND: Aberrations in MYC underlie a large proportion of liver hepatocellular carcinoma (LIHC) cases; however, MYC is difficult to target because of its undruggable structure. We aimed to uncover MYC-associated molecular targets to provide new strategies for LIHC treatment. METHODS: LIHC transcriptome datasets and clinical information were obtained from The Cancer Genome Atlas. A series of bioinformatics analyses were performed for 370 patients who were stratified based on the median MYC expression level (high-MYC group and low-MYC group). Correlation analysis was performed to determine relationships between the expression of key MYC-associated genes and prognosis, DNA promotor methylation, and immune cell infiltration. Gene ontology and Kyoto Encyclopedia of Genes and Genomes Pathway enrichment analyses were performed to elucidate the functions of these genes in LIHC. Their expression and functions in LIHC were further verified using transgenic mice overexpressing c-Myc under control of the hepatocyte-specific promoter (Alb-Cre). RESULTS: AURKB, CCNB2, and CDKN3 were overexpressed in LIHC patients with high MYC expression and were associated with poor prognosis. Upregulation of these 3 genes was significantly correlated with hypomethylated promoter status, advanced T stage, metastasis, and immune cell infiltration in LIHC patients. Functional enrichment analyses indicated that these genes participate in the "p53 signaling pathway" and "cell cycle". Furthermore, RT-PCR and IHC analysis revealed that their mRNA and protein expression levels were upregulated in an Alb-Cre;cMYClsl/- mouse model. Drugs that target these 3 MYC-related genes were identified. CONCLUSION: Taken together, our results identify biomarkers of potential utility for managing liver cancer therapy owing to their significance in tumorigenesis, proliferation, and tumor immunity.

Scientific research competitiveness in hospitals: A narrative review of major hospital ranking systems in China.

Background and Aims: Several hospital ranking systems have been created in China recently, but there is still a lack of comprehensive analysis of the weight and significance of scientific research in hospital ranking. The present study aimed to identify and analyze the role of scientific research competitiveness in various hospital ranking systems in China. Methods: Over 200 materials published between 2010 and 2020 and related to three mainstream hospital ranking systems in China were reviewed. The methodologies applied in the three ranking systems were analyzed and compared. In addition, the comparative learning and analysis of Top 10 and Top 46-55 hospitals according to the ranking system of China's Best Hospital Rankings was performed for a longitudinal study. Results: The three major hospital rankings had different scientific research capability ranking methodologies and emphases of scientific research evaluation systems. The most commonly used indicators were science citation index (SCI) publications, National Scientific Foundation of China funding, a number of national key laboratories, and a number of academicians. The relative standing of several top hospitals showed slightly different in the three major Chinese hospital ranking systems. For the longitudinal study, we found that the fluctuation of the ranking of the Top 46-55 hospitals was significantly higher than that of the Top 10 hospitals, in which scientific research played a vital role. Conclusion: The proportion of scientific research plays an important role in the hospital ranking systems. The quality and quantity of SCI publications, the key indicators of national projects, and top academic talents are the most important factors used to evaluate the level of hospital scientific research, and thus affect the ranking of hospitals.

Effect of low-dose radiation on thyroid function and the gut microbiota.

BACKGROUND: The thyroid-gut axis has a great influence on the maintenance of human health; however, we know very little about the effects of low-dose ionizing radiation (LDR) on thyroid hormone levels and gut microbiota composition. AIM: To investigate the potential effects of low-dose X-ray radiation to male C57BL/6J mice. METHODS: Peripheral blood was collected for enzyme-linked immunosorbent assay (ELISA), and stool samples were taken for 16S ribosomal RNA (rRNA) gene sequencing after irradiation. RESULTS: We found that LDR caused changes in thyroid stimulating hormone (TSH) levels in the irradiated mice, suggesting a dose-dependent response in thyroid function to ionizing radiation. No changes in the diversity and richness of the gut microbiota were observed in the LDR-exposed group in comparison to the controls. The abundance of Moraxellaceae and Enterobacteriaceae decreased in the LDR-exposed groups compared with the controls, and the Lachnospiraceae abundance increased in a dose-dependent manner in the radiated groups. And the abundances of uncultured_bacterium_g_Acinetobacter, uncultured_bacterium_ o_Mollicutes_RF39, uncultured_bacterium_g_Citrobacter, and uncultured_ bacterium_g_Lactococcus decreased in the radiated groups at the genus level, which showed a correlation with radiation exposure and diagnostic efficacy. Analysis of functional metabolic pathways revealed that biological metabolism was predicted to have an effect on functional activities, such as nucleotide metabolism, carbohydrate metabolism, and glycan biosynthesis and metabolism. Furthermore, Kyoto Encyclopedia of Genes and Genomes pathway annotation also suggested that changes in the gut microbiota were related to processing functions, including translation, replication and repair. CONCLUSION: LDR can change thyroid function and the gut microbiota, and changes in the abundances of bacteria are correlated with the radiation dose.

microRNA-873 inhibits self-renewal and proliferation of pancreatic cancer stem cells through pleckstrin-2-dependent PI3K/AKT pathway.

Recent studies have emphasized microRNAs (miRs) as crucial regulators in the occurrence and development of pancreatic cancer that continues to be one of the deadliest malignancies with few effective therapies. The study aimed to investigate the functional role of miR-873 and its associated mechanism to unravel the biological characteristics of pancreatic cancer stem cells in tumor growth. The expression patterns of pleckstrin-2 (PLEK2) and miR-873 were detected in the pancreatic cancer tissues. Then to further investigate specific role of miR-873, the pancreatic cancer stem cells were treated with miR-873 mimic, PLEK2, small interfering RNA against PLEK2, LY294002 (inhibitor of phosphatidylinositol 3-kinase/protein kinase B [PI3K/AKT] pathway) to detect the relative gene expression as well as their effects on cell self-renewal, proliferation and apoptosis. Finally, the tumor formation in nude mice was measured to verify the preceding results in vivo. Pancreatic cancer tissues exhibited a decline of miR-873 expression and an enhancement of PLEK2 expression. miR-873 targeted PLEK2 and downregulated its expression, leading to inhibition of PI3K/AKT pathway. Overexpressed miR-873 or silenced PLEK2 inhibited the self-renewal and proliferation while promoting the apoptosis of pancreatic cancer stem cells. Tumor formation was inhibited by overexpressed miR-873 or silenced PLEK2 in nude mice. Overall, miR-873 can suppress the self-renewal and proliferation of pancreatic cancer stem cells by blocking PLEK2-dependent PI3K/AKT pathway. Hence, this study contributes to understanding the role of miR-873 in pancreatic cancer stem cells and its underlying molecular mechanisms to aid in the development of effective pancreatic cancer therapeutics.

MiR-9-1 Suppresses Cell Proliferation and Promotes Apoptosis by Targeting UHRF1 in Lung Cancer.

Lung cancer is listed as the most common reason for cancer-related death all over the world despite diagnostic improvements and the development of chemotherapy and targeted therapies. MicroRNAs control both physiological and pathological processes including development and cancer. A microRNA-9 to 1 (miR-9 to 1) overexpression model in lung cancer cell lines was established and miR-9 to 1 was found to significantly suppress the proliferation rate in lung cancer cell lines, colony formation in vitro, and tumorigenicity in nude mice of A549 cells. Ubiquitin-like containing PHD and RING finger domains 1 (UHRF1) was then identified to direct target of miR-9 to 1. The inhibition of UHRF1 by miR-9 to 1 causes G1 arrest and p15, p16, and p21 were re-expressed in miR-9 to 1 group in mRNA level and protein level. Silence of UHRF1 expression in A549 cells resulted in the similar re-expression of p15, p16, p21 which is similar with miR-9 to 1 infection. Therefore, we concluded that UHRF1 is a new target for miR-9 to 1 to suppress cell proliferation by re-expression of tumor suppressors p15, p16, and p21 mediated by UHRF1.