• Benign Disease
• Cancer
• DNA Methylation
• Gastrointestinal Disease
• Methylated Biomarkers

• Humans
• DNA Methylation
• Epigenesis, Genetic
• Gastrointestinal Neoplasms/genetics
• Gastrointestinal Neoplasms/pathology
• Gastrointestinal Diseases/genetics
• Phenotype
• Precancerous Conditions/genetics
• Precancerous Conditions/pathology
• Precancerous Conditions/metabolism
• Animals
• Genetic Predisposition to Disease
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Risk Factors

• R01 CA287294 NCI NIH HHS
• R01 DK118250 NIDDK NIH HHS
• UG3 CA211457 NCI NIH HHS
• UH3 CA211457 NCI NIH HHS

• Exposome
• Intraductal papillary mucinous neoplasm
• Metabolomics
• MicroRNA
• Polymorphisms

• Humans
• Biomarkers, Tumor/genetics
• Pancreatic Neoplasms/pathology
• Pancreatic Neoplasms/genetics
• Pancreatic Neoplasms/diagnosis
• Pancreatic Neoplasms/metabolism
• Disease Progression
• Carcinoma, Pancreatic Ductal/pathology
• Carcinoma, Pancreatic Ductal/genetics
• Carcinoma, Pancreatic Ductal/metabolism
• Carcinoma, Pancreatic Ductal/diagnosis
• Pancreatic Intraductal Neoplasms/pathology
• Pancreatic Intraductal Neoplasms/genetics
• Pancreatic Intraductal Neoplasms/metabolism
• Pancreatic Intraductal Neoplasms/diagnosis
• Genomics/methods
• Adenocarcinoma, Mucinous/pathology
• Adenocarcinoma, Mucinous/metabolism
• Metabolomics/methods
• Proteomics/methods
• Multiomics

• PDAC
• apoptosis
• cell cycle
• microRNA (miRNA)
• pancreatic cancer
• proliferation
• signaling pathways

• HOXC4
• cell proliferation
• glycolysis
• lactate dehydrogenase A
• pancreatic cancer

• Animals
• Female
• Humans
• Male
• Mice
• Apoptosis/genetics
• Cell Line, Tumor
• Cell Proliferation/genetics
• Gene Expression Regulation, Neoplastic
• Glycolysis/genetics
• Homeodomain Proteins/genetics
• Homeodomain Proteins/metabolism
• L-Lactate Dehydrogenase/metabolism
• L-Lactate Dehydrogenase/genetics
• Mice, Nude
• Pancreatic Neoplasms/pathology
• Pancreatic Neoplasms/genetics
• Pancreatic Neoplasms/metabolism

• Combined immunotherapy
• Immunotherapy
• Pancreatic cancer
• Resistance
• Tumor microenvironment
• manipulation

• long non-coding RNA
• microRNA
• microbiome
• pancreatic ductal adenocarcinoma

• Cancer
• Diagnostic and prognostic significance
• HOX genes
• Metastasis
• Signaling pathways

• Carcinogenesis/genetics
• Cell Transformation, Neoplastic/genetics
• Genes, Homeobox/genetics
• Humans
• Neoplasms/metabolism
• Signal Transduction/genetics

• IA/CPHI/18/1/503927 The Wellcome Trust DBT India Alliance
• Manipal Academy of Higher Education, Manipal

• fibroblasts
• scleroderma
• systemic
• systemic sclerosis

• Cells, Cultured
• Fibroblasts/metabolism
• Fibroblasts/pathology
• Gene Expression Regulation/physiology
• Humans
• Kruppel-Like Factor 4/genetics
• Kruppel-Like Factor 4/metabolism
• MicroRNAs/metabolism
• Scleroderma, Systemic/genetics
• Scleroderma, Systemic/metabolism
• Scleroderma, Systemic/pathology
• Skin/metabolism
• Skin/pathology
• T-Box Domain Proteins/metabolism
• Transcription Factor AP-2/metabolism
• Transcriptome

• K01 AR067280 NIAMS NIH HHS
• K24 AR060297 NIAMS NIH HHS
• R35 HL144979 NHLBI NIH HHS
• T32 AR050958 NIAMS NIH HHS

Pancreatic ductal adenocarcinoma’s (PDAC) dismal prognosis is associated with its aggressive biological behavior and resistance to chemotherapy. Epithelial to mesenchymal transition (EMT) has been recognized as a key driver of PDAC progression and development of drug resistance. EMT is a transient and reversible process leading to transdifferentiation of epithelial cells into a more mesenchymal phenotype. It is regulated by multiple signaling pathways that control the activity of a transcription factors network. Activation of EMT in pre-invasive stages of PDAC has been accused for early dissemination. Furthermore, it contributes to the development of intratumoral heterogeneity and drug resistance. This review summarizes the available data regarding signaling networks regulating EMT and describes the integral role of EMT in different aspects of PDAC pathogenesis.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies, characterized by aggressive biological behavior and a lack of response to currently available chemotherapy. Emerging evidence has identified epithelial to mesenchymal transition (EMT) as a key driver of PDAC progression and a central regulator in the development of drug resistance. EMT is a reversible transdifferentiation process controlled by complex interactions between multiple signaling pathways such as TGFb, Wnt, and Notch, which converge to a network of specific transcription factors. Activation of EMT transcriptional reprogramming converts cancer cells of epithelial differentiation into a more mesenchymal phenotypic state. EMT occurrence in pre-invasive pancreatic lesions has been implicated in early PDAC dissemination. Moreover, cancer cell phenotypic plasticity driven by EMT contributes to intratumoral heterogeneity and drug tolerance and is mechanistically associated with the emergence of cells exhibiting cancer stem cells (CSCs) phenotype. In this review we summarize the available data on the signaling cascades regulating EMT and the molecular isnteractions between pancreatic cancer and stromal cells that activate them. In addition, we provide a link between EMT, tumor progression, and chemoresistance in PDAC.

• cancer stem cells
• chemoresistance
• epithelial to mesenchymal transition
• intratumor heterogeneity
• pancreatic ductal adenocarcinoma
• tumor microenvironment

• miRNA
• pancreatic cancer
• therapeutic potential

Objectives: This study was designed to identify a messenger RNA (mRNA) expression signature to predict survival in patients with oral squamous cell carcinoma (OSCC).

Methods: mRNA expression profiles were integrated with clinical data from 280 samples, including 19 normal tissues and 261 OSCC tissues in The Cancer Genome Atlas. We identified differentially expressed mRNAs (DEmRNAs) between the OSCC and normal tissue samples and developed a novel mRNA-focused expression signature using a Cox regression analysis and other bioinformatic methods. The prognostic value of this signature was evaluated by Kaplan–Meier analysis, multivariable COX regression, and receiver operating characteristic (ROC) curve analysis. Protein–protein interaction (PPI) network, gene ontology, and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were performed to predict the function of the DEmRNAs. Signature-related mRNAs were analyzed by gene set enrichment analyses (GSEA) and validated by quantitative real-time polymerase chain reaction (qRT-PCR) in 20 paired OSCC and adjacent healthy tissues.

Results: We identified a novel 5-mRNA expression signature (HOXA1, CELSR3, HIST1H3J, ZFP42, and ASCL4) that could predict patient outcomes in OSCC. The risk score based on the signature was able to separate OSCC patients into high- and low-risk groups that showed significantly different overall survival (p < 0.001, log-rank test). The signature was further validated as an effective independent prognostic predictor of OSCC by multivariate Cox regression analysis (hazard ratio = 3.747, confidence interval: 2.279–5.677, p < 0.001) and ROC curve of the third year (area under the curve = 0.733). Functional analysis demonstrated that the key hub genes in the PPI network were mainly enriched in cell division, cell proliferation, and the p53 signaling pathway. GSEA results showed that the 5 mRNAs were significantly enriched in mismatch repair, DNA replication, and the NOTCH signaling pathway. Finally, qRT-PCR results showed that the 5 mRNAs were upregulated in OSCC tissue in agreement with the predictions from our bioinformatics analysis.

Conclusions: We identified a novel 5-mRNA signature that could predict the survival of patients with OSCC and may be a promising biomarker for personalized cancer treatments.

• bioinformatics analysis
• mRNA signature
• oral squamous cell carcinoma

• Circular RNA
• Long non-coding RNA
• MicroRNA
• Non-coding RNAs
• Pancreatic ductal adenocarcinoma

• Animals
• Cell Proliferation/physiology
• Female
• Humans
• MAP Kinase Signaling System
• Mice
• Neoplasm Metastasis
• Pancreatic Neoplasms/genetics
• Pancreatic Neoplasms/metabolism
• Pancreatic Neoplasms/pathology
• Proto-Oncogene Proteins c-akt/metabolism
• RNA, Long Noncoding/genetics
• RNA, Long Noncoding/metabolism
• Survival Analysis
• Transfection

New biomarkers are needed to further stratify the risk of malignancy in intraductal papillary mucinous neoplasm (IPMN). Although microRNAs (miRNAs) are expected to be stable biomarkers, they can vary owing to a lack of definite internal controls. To identify universal biomarkers for invasive IPMN, we performed miRNA sequencing using tumor-normal paired samples. A total of 19 resected tissues and 13 pancreatic juice samples from 32 IPMN patients were analyzed for miRNA expression by next-generation sequencing with a two-step normalization of miRNA sequence data. The miRNAs involved in IPMN associated with invasive carcinoma were identified from this tissue analysis and further verified with the pancreatic juice samples. From the tumor-normal paired tissue analysis of the expression levels of 2792 miRNAs, 20 upregulated and 17 downregulated miRNAs were identified. In IPMN associated with invasive carcinoma (INV), miR-10a-5p and miR-221-3p were upregulated and miR-148a-3p was downregulated when compared with noninvasive IPMN. When these findings were further validated with pancreatic juice samples, miR-10a-5p was found to be elevated in INV (p = 0.002). Therefore, three differentially expressed miRNAs were identified in tissues with INV, and the expression of miR-10a-5p was also elevated in pancreatic juice samples with INV. MiR-10a-5p is a promising additional biomarker for invasive IPMN.

• formalin-fixed paraffin-embedded samples
• intraductal papillary mucinous neoplasm
• miRNA
• next-generation sequencing
• pancreatic juice

Hox genes, a highly conserved homolog in most animals, play vital functions in cell development and organ formation. In recent years, researchers have discovered that it can act as a tumor regulator, and its members can participate in tumorigenesis by regulating receptor signaling, cell differentiation, apoptosis, migration, EMT, and angiogenesis. Hox genes and which major members play a vital role in the progress of head and neck squamous cell carcinoma (HNSCC) is still unclear. After analyzing the expression differences and prognostic value of all Hox genes through the TCGA-HNSC database, we use histochemistry stains in 52 pairs of HNSCC slices to verify the expression level of the key member-HOXA1. In correlation analysis, we found that high HOXA1 expression is related to poor pathological grade (p = 0.0077), advanced T stage (p = 0.021) and perineural invasion (PNI) (p = 0.0019). Furthermore, we used Cox univariate and multivariate regression analysis to confirm the independent predictive power of HOXA1 expression. To explore the underlying mechanisms behind HOXA1, we ran GSVA and GSEA and found fourteen mutual signaling pathways, including neuroprotein secretion and transport, tumor-associated signaling pathways, cell adhere junction and metabolic reprogramming. Finally, we found that the high expression of HOXA1 is significantly related to the decrease of CD8+ T cell infiltration and the decline of DNA methylation level. Our findings demonstrated that HOXA1, as a notable member of the HOX family, maybe an independent prognostic indicator in HNSCC.

• biomarker
• head and neck squamous cell carcinoma
• homeobox A1
• hox genes
• perineural invasion
• prognosis
• tumor

Pancreatic cancer is a high incidence, high degree of malignancy, and high mortality in the digestive system tumor. The incidence of pancreatic cancer in China has increased nearly six folds in the past 20 years, ranking fifth in the mortality rate of malignant tumors, so it is particularly important to actively explore clinical indicators with better diagnostic significance for pancreatic cancer. LncRNA performs an essential regulatory function in the occurrence, development, and metastasis of many kinds of tumors, playing both a carcinogenic role and a tumor suppressor gene. Here, we demonstrated the function and mechanism of LncRNA-XLOC_012370 in the development of pancreatic cancer. In our research, the abnormal upregulation of XLOC_012370 was observed in pancreatic cancer patients’ tumor tissues. XLOC_012370 was related to tumor stage, lymph node metastasis, and overall survival. Silencing of XLOC_012370 prevented the proliferation, migration, and invasion via the NF-κB signal pathway. Further, miR-140-5p was identified as the target and downstream of XLOC_012370 and involved in pancreatic cancer progression. In vivo, knockdown of XLOC_012370 inhibited tumor growth via the NF-κB signal pathway. In conclusion, lncRNA-XLOC_012370 is closely related to some malignant clinicopathological features and prognosis of pancreatic cancer. Thus the miR-140-5p/NF-κB signal pathway might represent a promising treatment strategy to combat pancreatic cancer.

• NF-κB signal pathway
• TLR4
• lncRNA-XLOC_012370
• miR-140-5p
• pancreatic cancer

• HMGA2/TET1/HOXA signalling pathway
• HOX
• TGFβ signalling
• epithelial-to-mesenchymal transition
• invasion and metastasis
• lncRNAs
• microRNAs

• colorectal cancer
• exosome
• microenvironment
• lung fibroblasts
• microRNA‑10a

• Hippo signaling pathway
• WW and C2 domain containing 2
• microRNA-10a
• pancreatic cancer

• HOX genes
• embryogenesis
• hallmarks of cancer
• transcription factors

Non-coding RNAs (ncRNAs) are reported to be expressed in human cancers, including pancreatic ductal adenocarcinoma (PDAC). These ncRNAs affect the growth, migration and invasion of tumor cells by regulating cell cycle and apoptosis, as well as playing important roles in epigenetic processes, transcription and post-transcriptional regulation. It is still unclear whether alterations in ncRNAs influence PDAC development and progression. Because of this, analysis based on existing data on ncRNAs, which are crucial for modulating pancreatic tumorigenesis, will be important for future research on PDAC. Here, we summarize ncRNAs with tumor-promoting functions: HOTAIR, HOTTIP, MALAT1, lncRNA H19, lncRNA PVT1, circ-RNA ciRS-7, circ-0030235, circ-RNA_100782, circ-LDLRAD3, circ-0007534, circRHOT1, circZMYM2, circ-IARS, circ-RNA PDE8A, miR-21, miR-155, miR-221/222, miR-196b, miR-10a. While others including GAS5, MEG3, and lncRNA ENST00000480739, has_circ_0001649, miR-34a, miR-100, miR-217, miR-143 inhibit the proliferation and invasion of PDAC. Hence, we summarize the functions of ncRNAs in the occurrence, development and metastasis of PDAC, with the goal to provide guidance in the clinical diagnosis and treatment of PDAC.

• circ-RNA
• lncRNA
• miRNA
• non-coding RNAs
• pancreatic ductal adenocarcinoma

Solid pseudopapillary neoplasm (SPN) of pancreas is a rare pancreatic neoplasm with a low metastatic potential. Up to 10% of patients with localized disease at presentation will develop systemic metastases, usually in the peritoneum or the liver. Due to the rarity of SPNs and the overall excellent prognosis, reliable prognostic factors to predict malignant biological behavior remain undetermined. Therefore, we aimed to define clinical, histological, and microRNA patterns that are associated with metastatic disease. We conducted a retrospective single center study on all patients operated for SPN of pancreas between 1995 and 2018. Clinical and pathological data were collected, and expression patterns of 2,578 human microRNAs were analyzed using microRNA array (Affimetrix 4.1) in normal pancreases (NPs), localized tumors (LTs), and metastatic tumors (MTs). The diagnosis of SPN was confirmed in 35 patients who included 28 females and 3 males, with a mean age of 33.8 ± 13.9 years. The only clinical factor associated with metastases was tumor size (mean tumor size 5.20 ± 3.78 in LT vs. 8.13± 1.03 in MT, p < 0.012). Microscopic features of malignancy were not associated with metastases, nor were immunohistochemical stains, including the proliferative index KI67. Higher expressions of miR-184, miR-10a, and miR-887, and lower expressions of miR-375, miR-217, and miR-200c were observed in metastatic tissues on microarray, and validated by real-time polymerase chain reaction. Hierarchal clustering demonstrated that the microRNA expression pattern of MTs was significantly different from that of LTs. The only clinical factor associated with metastases of SPN of pancreas was tumor size. Histological features and immunohistological staining were not predictive of metastases. A panel of six microRNAs was differentially expressed in MTs, and these findings could potentially be used to predict tumor behavior. Validation of these results is needed in larger series.

• metastasis
• microRNA
• pancreatic cancer
• prognostic factors
• solid pseudopapillary neoplasm (SPN)

• metastasis
• metastasis models
• pancreatic cancer

• Carcinoma, Pancreatic Ductal/epidemiology
• Carcinoma, Pancreatic Ductal/genetics
• Disease Progression
• Epithelial-Mesenchymal Transition
• Humans
• Neoplasm Metastasis
• Pancreatic Neoplasms/epidemiology
• Pancreatic Neoplasms/genetics
• Prognosis
• Survival Rate
• Pancreatic Neoplasms

• R01 CA267870 NCI NIH HHS

Pancreatic ductal adenocarcinoma (PDAC) is considered as one of the most aggressive cancers lacking efficient early detection biomarkers. Circulating miRNAs are now being considered to have potency to be used as diagnostic and prognostic biomarkers in different diseases as well as cancers. In case of cancer, a fraction of the circulating miRNAs is actually derived from the tumour tissue. This fraction would function as stable biomarker for the disease and also would contribute to the understanding of the disease development. There are not many studies exploring this aspect in pancreatic cancer and even there is not much overlap of results between existing studies.

In order to address that gap, we performed a miRNA microarray analysis to identify differentially expressed circulating miRNAs between PDAC patients and normal healthy individuals and also found two more similar datasets to perform a meta-analysis using a total of 182 PDAC patients and 170 normal, identifying a set of miRNAs significantly altered in patient serum. Next, we found five datasets studying miRNA expression profile in tumour tissues of PDAC patients as compared to normal pancreas and performed a second meta-analysis using data from a total of 183 pancreatic tumour and 47 normal pancreas to detect significantly deregulated miRNAs in pancreatic carcinoma. Comparison of these two lists and subsequent search for their target genes which were also deregulated in PDAC in inverse direction to miRNAs was done followed by investigation of their role in disease development.

We identified 21 miRNAs altered in both pancreatic tumour tissue and serum. While deciphering the functions of their target genes, we characterized key miR-Gene interactions perturbing the biological pathways. We identified important cancer related pathways, pancreas specific pathways, AGE-RAGE signaling, prolactin signaling and insulin resistance signaling pathways among the most affected ones. We also reported the possible involvement of crucial transcription factors in the process.

Our study identified a unique meta-signature of 21 miRNAs capable of explaining pancreatic carcinogenesis and possibly holding the potential to act as biomarker for the disease detection which could be explored further.

• Meta-analysis
• Pancreatic ductal adenocarcinoma
• Serum
• Tumour
• microRNA

The circadian rhythm of the liver plays an important role in maintaining its metabolic homeostasis. We performed comprehensive expression analysis of microRNAs (miRNAs) using TaqMan polymerase chain reaction of liver biopsy tissues to identify the miRNAs that are significantly up‐regulated in advanced chronic hepatitis C (CHC). We found miR‐10a regulated various liver metabolism genes and was markedly up‐regulated by hepatitis C virus infection and poor nutritional conditions. The expression of miR‐10a was rhythmic and down‐regulated the expression of the circadian rhythm gene brain and muscle aryl hydrocarbon receptor nuclear translocator‐like 1 (Bmal1) by directly suppressing the expression of RA receptor‐related orphan receptor alpha (RORA). Overexpression of miR‐10a in hepatocytes blunted circadian rhythm of Bmal1 and inhibited the expression of lipid synthesis genes (sterol regulatory element binding protein [SREBP]1, fatty acid synthase [FASN], and SREBP2), gluconeogenesis (peroxisome proliferator‐activated receptor gamma coactivator 1 alpha [PGC1α]), protein synthesis (mammalian target of rapamycin [mTOR] and ribosomal protein S6 kinase [S6K]) and bile acid synthesis (liver receptor homolog 1 [LRH1]). The expression of Bmal1 was significantly correlated with the expression of mitochondrial biogenesis‐related genes and reduced Bmal1 was associated with increased serum alanine aminotransferase levels and progression of liver fibrosis in CHC. Thus, impaired circadian rhythm expression of Bmal1 by miR‐10a disturbs metabolic adaptations, leading to liver damage, and is closely associated with the exacerbation of abnormal liver metabolism in patients with advanced CHC. In patients with hepatitis C‐related liver cirrhosis, liver tissue miR‐10a levels were significantly associated with hepatic reserve, fibrosis markers, esophageal varix complications, and hepatitis C‐related hepatocellular carcinoma recurrence. Conclusion: MiRNA‐10a is involved in abnormal liver metabolism in cirrhotic liver through down‐regulation of the expression of the circadian rhythm gene Bmal1. Therefore, miR‐10a is a possible useful biomarker for estimating the prognosis of liver cirrhosis.

• diagnosis
• microRNA
• pancreatic cancer
• potential therapeutic targets
• prognosis

• Animals
• Biomarkers, Tumor/genetics
• Gene Expression Regulation, Neoplastic
• Humans
• MicroRNAs/genetics
• Pancreatic Neoplasms/diagnosis
• Pancreatic Neoplasms/genetics
• Pancreatic Neoplasms/therapy
• RNAi Therapeutics/methods

Background: Oral cancer is one of the most frequent solid cancers worldwide, and oral squamous cell carcinoma (OSCC) constitutes approximately 90% of oral cancers. The discovery of reliable prognostic indicators would be a potential strategy for OSCC treatment. In the present study, we aim to explore the underlying mechanism by which microRNA-145 (miR-145) affected OSCC. Methods: Forty-eight patients diagnosed with OSCC were enrolled to obtain the OSCC tissues and adjacent normal tissues. The targeting relationship between miR-145 and Homeobox A1 (HOXA1) was verified. In order to assess the effects of miR-145 in OSCC and the detailed regulatory mechanism, the SCC-9 cell line was adopted, in which expression of miR-145 and HOXA1 were altered by transfection. Then, a series of in vitro and in vivo experiments were performed to evaluate the cell viability, migration, invasion, and tumor growth. Results: miR-145 was poorly expressed and HOXA1 was highly expressed in OSCC. HOXA1 was verified as a target of miR-145 to mediate the activation of the extracellular signal-regulated kinase/mitogen activated protein kinase (ERK/MAPK) signaling pathway. In the circumstance of miR-145 elevation or HOXA1 depletion, the SCC-9 cell line manifested with inhibited cell viability, invasion, and migration in vitro, coupled with reduced tumor growth in vivo, with a decreased expression of ERK/MAPK signaling pathway-related genes/proteins. Conclusion: These findings suggested that miR-145 can inhibit HOXA1 to inactivate the ERK/MAPK signaling pathway, thereby suppressing OSCC cell proliferation, migration, and invasion to further inhibit the development of OSCC, highlighting a novel therapeutic target for the OSCC treatment.

• Extracellular-signal-regulated kinase/mitogen activated protein kinase
• Homeobox A1
• MicroRNA-145
• Oral squamous cell carcinoma

The Hox gene family plays an important role in organogenesis and animal development. Currently, 39 Hox genes that are clustered in four chromosome regions have been identified in humans. Emerging evidence suggests that Hox genes are involved in the development of the pancreas. However, the expression of Hox genes in pancreatic tumor tissues has been investigated in only a few studies. In addition, whether specific Hox genes can promote or suppress cancer metastasis is not clear. In this article, we first review the recent progress in studies on the role of Hox genes in pancreatic cancer. By comparing the expression profiles of pancreatic cancer cells isolated from genetically engineered mice established in our laboratory with three different proliferative and metastatic abilities, we identified novel Hox genes that exhibited tumor-promoting activity in pancreatic cancer. Finally, a potential oncogenic mechanism of the Hox genes was hypothesized.

• Hox genes
• genetically engineered mouse
• pancreas development
• pancreatic cancer

Liver cancer is a malignant tumor that threatens human health worldwide. It has poor prognosis rates and ineffective therapeutic options. Recently, various miRNAs have been proven to exert promoting or inhibiting functions in different malignancies. However, the definitive mechanisms of miR-99a in liver cancer remain unclear. In the current study, we explored the relationships between the expression of miR-99a and HOXA1 in liver cancer tissues and cells to explore their combined effects on the occurrence and metastasis of liver cancer. The expression of miR-99a and HOXA1 in liver cancer tissue samples and cells was measured by RT-qPCR. Following transfection, transwell assays were conducted to assess the invasion and migration capacities of liver cancer cells. Subsequently, western blots and luciferase reporter assays were performed in liver cancer cells to identify the target of miR-99a. The data indicated that miRNA-99a expression was significantly reduced in both liver cancer tissue samples and cells compared with normal tissues and normal liver cells respectively. By contrast, the HOXA1 expression levels in liver cancer tissues and cells were significantly increased in contrast to the control group. The findings also revealed that the miR-99a expression was negatively correlated with HOXA1 expression in liver cancer tissue samples and miR-99a could suppress cell invasion and migration by targeting HOXA1 in liver cancer.

• HOXA1
• invasion
• liver cancer
• miR-99a
• migration

• Diagnostic marker
• PTC
• Plasma microRNA
• qRT-PCR

• Her2/Neu+ breast carcinoma
• MiRNA-10
• MicroRNA profiling
• Oncogene
• Salivary duct carcinoma

MicroRNAs (miRNAs) have been reported to play vital roles in liver regeneration. Previous studies mainly focused on the functions of intracellular miRNAs, while the functions of circulating exosomal miRNAs in liver regeneration remain largely unknown. The aim of this study was to identify the key exosomal miRNA that played vital roles in liver regeneration.

The Sprague–Dawley male rats were assigned to 70% partially hepatectomized group (n = 6) and sham surgery group (n = 6). The peripheral blood of both groups was collected 24 h after surgery. The exosomal miRNAs were extracted, and microarray was used to find out the key miRNA implicated in liver regeneration. Adenovirus was used to overexpress the key miRNA in rats, and proliferating cell nuclear antigen (PCNA) staining was applied to study the effect of key miRNA overexpression on liver regeneration. Western blotting was used to validate the predicted target of the key miRNA.

Exosomal miR-10a was upregulated more than nine times in hepatectomized rats. The level of miR-10a was increased in the early phase of liver regeneration, reached the top at 72 h postsurgery, and decreased to perioperative level 168 h after surgery. Moreover, enforced expression of miR-10a by adenovirus facilitated the process of liver regeneration as evidenced by immunohistochemical staining of PCNA. Erythropoietin-producing hepatocellular receptor A4 (EphA4) has been predicted to be a target of miR-10a. The protein level of EphA4 was decreased in the early phase of liver regeneration, reached the bottom at 72 h postsurgery, and rose to perioperative level 168 h after surgery, which was negatively correlated with miR-10a, confirming that EphA4 served as a downstream target of miR-10a. Moreover, inhibition of EphA4 by rhynchophylline could promote the proliferation of hepatocytes by regulating the cell cycle.

Exosomal miR-10a might accelerate liver regeneration through downregulation of EphA4.

• Cell Cycle
• EphA4
• Liver Regeneration
• Microarray
• miR-10a

By regulating target genes, microRNAs play essential roles in carcinogenesis and drug resistance in human pancreatic ductal adenocarcinoma (PDAC). Previous studies have shown that microRNA-10a-5p (miR-10a-5p) is overexpressed in PDAC and acts as an oncogene to promote the metastatic behavior of PDAC cells. However, the role of miR-10a-5p in PDAC chemoresistance remains unclear.

The effects of miR-10a-5p on biological behaviors were analyzed. MiR-10a-5p and TFAP2C levels in tissues were detected, and the clinical value was evaluated.

We found that miR-10a-5p is up-regulated in gemcitabine-resistant PDAC cells and enhances PDAC cell gemcitabine resistance in vitro and vivo. Meanwhile, we also determined that miR-10a-5p promotes the migratory and invasive ability of PDAC cells. Next, we confirmed that transcription factor activating protein 2 gamma (TFAP2C) is a target of miR-10a-5p, and TFAP2C overexpression resensitizes PDAC cells to gemcitabine, which is initiated by miR-10a-5p. Further studies revealed that TFAP2C also decreased PDAC cell migration and invasion capability. Finally, survival analysis demonstrated that high miR-10a-5p expression levels and low TFAP2C expression levels were both independent adverse prognostic factors in patients with PDAC.

Together, these results indicate that miR-10a-5p/TFAP2C may be new therapeutic target and prognostic marker in PDAC.

The online version of this article (10.1186/s13046-018-0739-x) contains supplementary material, which is available to authorized users.

• Chemoresistance
• PDAC
• Prognosis
• TFAP2C
• miR-10a-5p

• biomarkers
• cohort studies
• microRNAs
• pancreatic cancer

• Adult
• Aged
• Area Under Curve
• Biomarkers, Tumor/blood
• Biomarkers, Tumor/genetics
• Carcinoma, Pancreatic Ductal/blood
• Carcinoma, Pancreatic Ductal/genetics
• Case-Control Studies
• Female
• Humans
• Male
• MicroRNAs/blood
• Middle Aged
• Pancreatic Neoplasms/blood
• Pancreatic Neoplasms/genetics
• Polymerase Chain Reaction
• Prospective Studies
• ROC Curve
• Sensitivity and Specificity

• U01 DK108323 NIDDK NIH HHS
• G0401527 Medical Research Council
• G1000143 Medical Research Council
• 16491 Cancer Research UK
• R01 CA075059 NCI NIH HHS
• 14136 Cancer Research UK
• 001 World Health Organization
• R37 CA075059 NCI NIH HHS
• MR/N003284/1 Medical Research Council

Analysis of our original microRNA (miRNA) expression signature of patients with advanced renal cell carcinoma (RCC) showed that microRNA‐10a‐5p (miR‐10a‐5p) was significantly downregulated in RCC specimens. The aims of the present study were to investigate the antitumor roles of miR‐10a‐5p and the novel cancer networks regulated by this miRNA in RCC cells. Downregulation of miR‐10a‐5p was confirmed in RCC tissues and RCC tissues from patients treated with tyrosine kinase inhibitors (TKI). Ectopic expression of miR‐10a‐5p in RCC cell lines (786‐O and A498 cells) inhibited cancer cell migration and invasion. Spindle and kinetochore‐associated protein 1 (SKA1) was identified as an antitumor miR‐10a‐5p target by genome‐based approaches, and direct regulation was validated by luciferase reporter assays. Knockdown of SKA1 inhibited cancer cell migration and invasion in RCC cells. Overexpression of SKA1 was observed in RCC tissues and TKI‐treated RCC tissues. Moreover, analysis of The Cancer Genome Atlas database demonstrated that low expression of miR‐10a‐5p and high expression of SKA1 were significantly associated with overall survival in patients with RCC. These findings showed that downregulation of miR‐10a‐5p and overexpression of the SKA1 axis were highly involved in RCC pathogenesis and resistance to TKI treatment in RCC.

• miR-10a-5p
• MicroRNA
• renal cell carcinoma
• spindle and kinetochore-associated protein 1
• tyrosine kinase inhibitor resistance

It has been demonstrated that microRNAs (miRNAs) act as oncogenes or tumor suppressors in a variety of cancers. Our previous work suggested that miR-10a/b functioned as a tumor suppressor in gastric cancer, and miR-10b was also reported to be significantly downregulated in advanced stage cervical cancer tissues. However, the aberrant expression of miR-10b in cervical cancer and its possible role in cervical carcinogenesis was largely unknown. In this study, we investigated the expression of miR-10b in cervical cancer tissues, carcinoma in situ tissues, mild dysplasia, moderate dysplasia, severe dysplasia tissues, and normal controls. We found that miR-10b was significantly downregulated during cervical cancer progression, and the lower level of miR-10b in cervical cancer was significantly associated with a more aggressive tumor phenotype. Moreover, overexpression of miR-10b in cervical cancer cells could inhibit the cell proliferation and invasion, and the further mechanism study suggested that its role was possibly through directly targeting HOXA1. These results suggested that the downregulation of miR-10b and the resulting elevated HOXA1 level in cervical cancer tissues might play critical roles in cervical cancer progression.