miR-214 inhibits invasion and migration via downregulating GALNT7 in esophageal squamous cell cancer

Tumor Biology - Previous studies verified that miR-214 is of great significance in the invasion and migration of a variety of cancers. It has been demonstrated that...     

miR-30b对结直肠癌细胞转移潜能的影响

  目的   明确miR-30b对结直肠癌细胞侵袭和迁移潜能的影响。   方法   RT-qPCR检测20对配对结直肠癌组织标本中miR-30b的表达;Transwell和划痕实验检测过表达和抑制miR-30b后结直肠癌细胞侵袭和迁移潜能的改变;应用生物信息学方法预测miR-30b的作用靶点;Western Blot及双荧光素酶报告基因实验验证过表达和抑制miR-30b后靶点Snail和EMT（epithelial mesenchymal transition）标志物的表达情况。   结果   癌组织中miR-30b表达水平明显低于正常肠黏膜组织;Transwell及划痕实验结果显示过表达miR-30b后结直肠癌细胞的侵袭迁移能力降低,抑制miR-30b后侵袭迁移能力增强;生物信息学预测结果显示miR-30b能够作用于Snail 3'-UTR,双荧光素酶检测结果进一步证实miR-30b能够作用于Snail 3'-UTR;Western Blot结果显示过表达miR-30b后Snail的表达下降,EMT标志物Vimentin表达下降和E-cadherin表达升高,而抑制miR-30b后结果相反。   结论   miR-30b在结直肠癌中表达水平下降,并通过靶向Snail调节结直肠癌细胞的侵袭和迁移。      

RhoC promotes metastasis via activation of the Pyk2 pathway in prostate cancer

RhoC is a member of the Ras-homologous family of genes which have been implicated in tumorigenesis and tumor progression. However, the exact role of RhoC is controversial and is yet to be clarified. We have examined the effect of RhoC on prostate tumor cells and found that RhoC had no effect on cell proliferation in vitro or on tumor growth in mice. However, RhoC significantly enhanced the metastatic ability of the tumor cells in these animals, suggesting that RhoC affects only the metastasis but not the growth of prostate tumor cells. The results of our immunohistochemical analyses on tumor specimens from 63 patients with prostate cancer indicate that RhoC expression had no significant correlation with Gleason grade. However, the expression of RhoC showed significant positive correlation with both lymph node and distant metastasis, and it was inversely correlated with patient survival. We also found that RhoC significantly augmented the invasion and motility of prostate tumor cells by activating matrix metalloproteinases 2 and 9 (MMP2 and MMP9) in vitro. The results of our antibody array analysis for signal molecules revealed that RhoC significantly activated kinases including mitogen-activated protein kinase (MAPK), focal adhesion kinase (FAK), Akt, and Pyk2. Inhibition of Pyk2 kinase blocked the RhoC-dependent activation of FAK, MAPK, and Akt, followed by the suppression of MMP2 and MMP9. Inhibitors of both MAPK and Akt also significantly blocked the activities of these MMPs. Therefore, our results indicate that RhoC promotes tumor metastasis in prostate cancer by sequential activation of Pyk2, FAK, MAPK, and Akt followed by the up-regulation of MMP2 and MMP9, which results in the stimulation of invasiveness of tumor cells.     

miR-185 and miR-133b deregulation is associated with overall survival and metastasis in colorectal cancer

Colorectal cancer (CRC) is one of the most common and deadly forms of cancer. Despite improved treatment modalities, post-operative recurrence and metastasis remain the major problems for extending patient survival after surgery. This highlights the need to search for biomarkers for prognostication and treatment stratification of colorectal cancer patients. In this study, we applied the SYBR-green quantitative PCR-based array approach to screen for differentially expressed miRNAs between patients with short (<50 months, range 10-33 months) and long survival (≥ 50 months, range 50-152 months). The selected candidate prognostic miRNAs were validated in a cohort of 50 CRC patients by TaqMan quantitative PCR. We found that high expression of miR-185 and low expression of miR-133b were correlated with poor survival (p=0.001 and 0.028, respectively) and metastasis (p=0.007 and 0.036, respectively) in colorectal cancer. Our findings suggest the potential prognostic values of these miRNAs for predicting clinical outcome after surgery.     

miR-199b-5p-DDR1-ERK signalling axis suppresses prostate cancer metastasis via inhibiting epithelial-mesenchymal transition

Background The investigation of underlying mechanism and the exploitation of novel therapies for metastatic prostate cancer (PCa) are still urgently needed. miR-199b-5p has been suggested to function as tumour suppressor in various human cancers. However, the clinical significance and role of miR-199b-5p in PCa remain unclear.Methods The current study sought to investigate the expression status of miR-199b-5p in PCa and the involved molecular mechanisms in PCa metastasis by using bioinformatics analyses, loss-and gain-of-functions and rescue experiments in vitro and in vivo.Results We demonstrated that miR-199b-5p was significantly downregulated in metastatic PCa tissues and cells when compared with the normal prostate tissue, the localised disease, the weakly metastatic and androgen-dependent PCa cell and the normal prostate epithelial cell. We also found that miR-199b-5p drastically suppressed PCa cell proliferation, migration and invasion in vitro and inhibited xenografts tumour growth and metastasis in vivo. Mechanistically, our results showed that miR-199b-5p could inhibit discoidin domain receptor tyrosine kinase 1 (DDR1) expression by directly targeting its 3’-UTR, thereby hindering epithelial-mesenchymal transition (EMT)-associated traits, which were induced by DDR1 activating ERK signalling pathway. Moreover, PCa patients with low miR-199b-5p expression level had a remarkably shorter overall survival than those with high miR-199b-5p level, indicating an association of miR-199b-5p loss with poor prognosis in patients with PCa. Furthermore, DDR1 was upregulated in PCa, and significantly correlated with high Gleason score, advanced pathological stage, tumour metastasis and shorter overall survival.Conclusions Our study, for the first time, provide evidence of a tumour-suppressive function of miR-199b-5p in the invasion and metastasis of PCa, supporting the translational exploitation of miR-199b-5p-based therapeutic approaches for PCa metastases. Also, the miR-199b-5p-DDR1-ERK signalling axis identified in this study represents a novel mechanism of regulating EMT in PCa metastases.Subject terms: Oncogenes, Prostate cancer     

miR-618抑制结直肠癌生长转移的机制探讨

目的:探讨miR-618在结直肠癌发生发展中的作用。方法:Real-time PCR法检测结直肠癌组织及Caco-2细胞中miR-618表达情况,改变结直肠癌细胞中miR-618表达,应用平板克隆实验检测转染后的结直肠癌细胞克隆能力,创伤愈合实验检测转染后的结直肠癌细胞迁移能力,Transwell小室实验检测转染后的结直肠癌细胞侵袭能力,Western Blotting法检测结直肠癌组织、细胞中SMAD4蛋白的表达变化情况及改变结直肠癌细胞中miR-618表达对SMAD4蛋白的影响。结果:结直肠癌组织及Caco-2细胞中miR-618表达较正常癌旁组织及FHC细胞明显下降（P＜0.05）,但SMAD4蛋白的表达增高（P＜0.05）。上调Caco-2细胞中miR-618表达后,Caco-2细胞的克隆、迁移及侵袭能力均减弱（P＜0.05）,但SMAD4蛋白表达下降（P＜0.05）。结论:miR-618通过下调SMAD4蛋白表达抑制结直肠癌生长转移。     

VEGF-activated miR-144 regulates autophagic survival of prostate cancer cells against Cisplatin

Tumor Biology - Cisplatin is a commonly used chemotherapy drug for prostate cancer (PC). However, some PCs are resistant to cisplatin treatment, while the molecular mechanisms underlying the...     

The tumour-suppressive function of miR-1 and miR-133a targeting TAGLN2 in bladder cancer

Background:

On the base of the microRNA (miRNA) expression signature of bladder cancer (BC), we found that miR-1 and miR-133a were significantly downregulated in BC. In this study, we focussed on the functional significance of miR-1 and miR-133a in BC cell lines and identified a molecular network of these miRNAs.

Methods and results:

We investigated the miRNA expression signature of BC clinical specimens and identified several downregulated miRNAs (miR-133a, miR-204, miR-1, miR-139-5p, and miR-370). MiR-1 and miR-133a showed potential role of tumour suppressors by functional analyses of BC cells such as cell proliferation, apoptosis, migration, and invasion assays. Molecular target searches of these miRNAs showed that transgelin 2 (TAGLN2) was directly regulated by both miR-1 and miR-133a. Silencing of TAGLN2 study demonstrated significant inhibitions of cell proliferation and increase of apoptosis in BC cell lines. The immunohistochemistry showed a positive correlation between TAGLN2 expression and tumour grade in clinical BC specimens.

Conclusions:

The downregulation of miR-1 and miR-133a was a frequent event in BC, and these miRNAs were recognised as tumour suppressive. TAGLN2 may be a target of both miRNAs and had a potential oncogenic function. Therefore, novel molecular networks provided by miRNAs may provide new insights into the underlying molecular mechanisms of BC.     

H19 non coding RNA-derived miR-675 enhances tumorigenesis and metastasis of breast cancer cells by downregulating c-Cbl and Cbl-b

H19 is a long non-coding RNA precursor of miR-675microRNA. H19 is increasingly described to play key roles in the progression and metastasis of cancers from different tissue origins. We have previously shown that the H19 gene is activated by growth factors and increases breast cancer cell invasion. In this study, we established H19/miR-675 ectopic expression models of MDA-MB-231 breast cancer cells to further investigate the underlying mechanisms of H19 oncogenic action. We showed that overexpression of H19/miR-675 enhanced the aggressive phenotype of breast cancer cells including increased cell proliferation and migration in vitro, and increased tumor growth and metastasis in vivo. Moreover, we identified ubiquitin ligase E3 family (c-Cbl and Cbl-b) as direct targets of miR-675 in breast cancer cells. Using a luciferase assay, we demonstrated that H19, through its microRNA, decreased both c-Cbl and Cbl-b expression in all breast cancer cell lines tested. Thus, by directly binding c-Cbl and Cbl-b mRNA, miR-675 increased the stability and the activation of EGFR and c-Met, leading to sustained activation of Akt and Erk as well as enhanced cell proliferation and migration. Our data describe a novel mechanism of protumoral action of H19 in breast cancer.     

Protease-activated receptor 1: a role in prostate cancer metastasis

Protease-activated receptor (PAR) 1, PAR3, and PAR4 are considered "thrombin receptors" because thrombin specifically cleaves the extracellular N-termini of the receptor to unmask a new amino acid terminus, which in turn acts as a peptide ligand by binding intramolecularly to the body of the receptor. Among those 3 family members, PAR1 is the predominant thrombin receptor. Although the thrombin-mediated regulation of clot formation has been studied extensively over the past decades, the possible role of thrombin in tumor metastasis via PAR1 has only recently received attention and is briefly discussed herein.     

Osteonectin promotes prostate cancer cell migration and invasion: a possible mechanism for metastasis to bone.

The mechanism underlying the "organ-specific" metastasis of prostate cancer cells to the bone is still poorly understood. It is not clear whether the cells only invade the bone and proliferate there or whether they invade many tissues but survive mainly in the bone ("seed and soil"). Extracts from various organs were used as chemoattractants in the in vitro chemotaxis and invasion assays. Results show that, in comparison with extracts of other tissues, bone extracts promote a 2- to 4-fold increase in chemotaxis by human prostate epithelial cells and a 4-fold increase in the invasive ability of human prostate carcinoma cells. The purified active factor from bone and from marrow stromal-cell-conditioned medium is a low glycosylated osteonectin that specifically promotes the invasive ability of bone-metastasizing prostate (and breast) cancer cells but not that of non-bone-metastasizing tumor cells. It does not stimulate the growth of prostate cancer cells in vitro or in vivo. Because osteonectin specifically enhances matrix metalloprotease activity in prostate and breast cancer cells (and not in other tumor cell types), we conclude that prostate cancer cell metastasis to the bone is, in part, mediated by the ability of osteonectin to promote migration, protease activity, and invasion.     

Tumour suppressors miR-1 and miR-133a target the oncogenic function of purine nucleoside phosphorylase (PNP) in prostate cancer

Background:

Our recent analyses of miRNA expression signatures showed that miR-1 and miR-133a were significantly reduced in several types of cancer. Interestingly, miR-1 and miR-133a are located on the same chromosomal locus in the human genome. We examined the functional significance of miR-1 and miR-133a in prostate cancer (PCa) cells and identified the novel molecular targets regulated by both miR-1 and miR-133a.

Methods and Results:

The expression levels of miR-1 and miR-133a were significantly downregulated in PCa compared with non-PCa tissues. Restoration of miR-1 or miR-133a in PC3 and DU145 cells revealed significant inhibition of proliferation, migration, and invasion. Molecular target identification by genome-wide gene expression analysis and luciferase reporter assay showed that purine nucleoside phosphorylase (PNP) was directly regulated by both miRNAs. Silencing of the PNP gene inhibited proliferation, migration, and invasion in both PC3 and DU145 cells. Immunohistochemistry detected positive staining of PNP in PCa specimens.

Conclusions:

Downregulation of miR-1 and miR-133a was a frequent event in PCa and both function as tumour suppressors. The PNP is a novel target gene of both miRNAs and potentially functions as an oncogene. Therefore, identification of novel molecular networks regulated by miRNAs may provide new insights into the underlying causes of PCa oncogenesis.     

Biological function and molecular mechanism of SRSF3 in cancer and beyond

Serine/arginine-rich splicing factor 3 (SRSF3; also known as SRp20), an important member of the family of SRSFs, is abnormally expressed in tumors, resulting in aberrant splicing of hub genes, such as CD44, HER2, MDM4, Rac family small GTPase 1 and tumor protein p53. Under normal conditions, the splicing and expression of SRSF3 are strictly regulated. However, the splicing, expression and phosphorylation of SRSF3 are abnormal in tumors. SRSF3 plays important roles in the occurrence and development of tumors, including the promotion of tumorigenesis, cellular proliferation, the cell cycle and metastasis, as well as inhibition of cell senescence, apoptosis and autophagy. SRSF3-knockdown significantly inhibits the proliferation and metastatic characteristics of tumor cells. Therefore, SRSF3 may be suggested as a novel anti-tumor target. The other biological functions of SRSF3 and its regulatory mechanisms are also summarized in the current review.