Yanping Gao

MicroRNAs as Regulators of Cisplatin Resistance in Lung Cancer

Cisplatin (CDDP) is one of the most effective broad-spectrum anticancer drugs, which has been employed for the treatment of lung cancer. The development of CDDP resistance is a major problem of tumor chemotherapy. MicroRNAs (miRNAs) are an abundant class of small non-protein-coding RNAs, involved in the initiation and progression of human cancer. Increasing evidence has shown that dysregulation of miRNAs is involved in chemo resistance of tumor cells to anti-cancer drugs, including CDDP. This article summarizes current research involving miRNAs as regulators of key target genes for CDDP resistance in lung cancer. Potential use of targeting miRNAs can lead to miRNA-based therapies, which will be helpful for overcoming drug resistance and developing more effective personalized anti-cancer treatment strategies in human lung cancers.

The role of microRNA-26a in human cancer progression and clinical application

MicroRNAs, a class of endogenous, small (18–25 nucleotides) noncoding RNAs, regulate gene expression by directly binding to the 3′-untranslated regions of target messenger RNAs. Evidence has shown that alteration of microRNAs is involved in cancer initial and progression. MicroRNA-26a is commonly dysregulated in diverse cancers and is involved in various biological processes, including proliferation, migration, invasion, angiogenesis, and metabolism by targeting multiple mRNAs. This review summarizes current research on the physiology and pathological functions of miR-26a and its applications for clinical therapy.

MiR-630 inhibits invasion and metastasis in esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC) is among the most aggressive malignancies and has a high incidence in China. MicroRNAs (miRNAs) are small endogenous RNAs that regulate multiple tumorigenic processes, including proliferation, invasion, metastasis and prognosis. Using miRNA expression profiling analysis, we found that miR-630 was markedly down-regulated in three ESCC tissue samples compared with that in paired normal esophageal tissues. Differential miR-630 expression was subsequently confirmed using quantitative real-time PCR. To determine whether miR-630 down-regulation could be considered as a diagnostic indicator and adverse prognostic factor, we investigated the association between miR-630 and clinicopathological characteristics in patients with ESCC. It was found that decreased miR-630 expression was associated with poor overall survival in these patients. In addition, we also explored the biological function of miR-630 by targeting Slug and investigated the correlation between miR-630 expression and epithelial-mesenchymal transition (EMT) progression in vivo and in vitro Ectopic miR-630 expression could inhibit proliferation, invasion and metastasis, whereas miR-630 knockdown induced proliferation, invasion, metastasis and EMT traits. Overall, our study supports a role for miR-630 as a critical novel modulator in ESCC.

The Emerging Role and Promise of Long Noncoding RNAs in Lung Cancer Treatment

Lung cancer is the leading cause of cancer death around the world. The advanced discovery of numerous long noncoding RNAs (lncRNAs) has dramatically changed the understanding of biology of human cancers, including lung cancer. LncRNAs are a group of noncoding RNAs (ncRNAs) with a length greater than 200 nucleotides with limited or no protein-coding capacity. Increasing evidence has shown that specific lncRNAs may be implicated in the process of tumorigenesis. Because of their roles in the regulation of multiple molecular pathways associated with changes in gene expression, lncRNAs can serve as potential diagnostic biomarkers or therapeutic targets in lung cancer. Importantly, dysregulated lncRNAs is reported to be correlated with the sensitivity of lung cancer cells to anticancer therapies, including chemotherapy, molecular-targeted therapy, etc. Herein, we review the recent progress of lncRNAs in lung cancer, with a particular focus on the multiple molecular roles of regulatory lncRNAs on the molecular signaling pathways involved in tumorigenesis and the resistance to such therapies.

MicroRNA-129 in Human Cancers: from Tumorigenesis to Clinical Treatment.

Emerging evidence has shown that microRNAs (miRNAs) play essential roles in regulating human cancers development and progression. However, the underlying mechanisms remain to be further explored. MiRNAs are a class of endogenous, non-coding, 18-24 nucleotide length single-strand RNAs that moderate gene expression primarily at post-transcriptional level. There is a growing body of literature that recognizes the importance of microRNA (miR)-129 during the development of cancers. Aberrant expression of miR-129 has been detected in various types of human cancers and the validated target genes are involved in cancer-related biological processes such as DNA methylation, cell proliferation, apoptosis, cell cycle, and metastasis. In this review, we summarized the roles of miR-129 family members and their target genes in tumorigenesis and clinical treatment of human cancers, highlighting the potential roles of miR-129 as biomarkers for cancer diagnosis and prognosis, and promising tools for cancer treatment.

A double-negative feedback loop between E2F3b and miR- 200b regulates docetaxel chemosensitivity of human lung adenocarcinoma cells.

MicroRNAs (miRNAs) are non-coding small RNAs which negatively regulate gene expressions mainly through 3′-untranslated region (3′-UTR) binding of target mRNAs. Recent studies have highlighted the feedback loops between miRNAs and their target genes in physiological and pathological processes including chemoresistance of cancers. Our previous study identified miR-200b/E2F3 axis as a chemosensitivity restorer of human lung adenocarcinoma (LAD) cells. Moreover, E2F3b was bioinformatically proved to be a potential transcriptional regulator of pre-miR-200b gene promoter. The existance of this double-negative feedback minicircuitry comprising E2F3b and miR-200b was confirmed by chromatin immunoprecipitation (ChIP) assay, site-specific mutation and luciferase reporter assay. And the underlying regulatory mechanisms of this feedback loop on docetaxel resistance of LAD cells were further investigated by applying in vitro chemosensitivity assay, colony formation assay, flow cytometric analysis of cell cycle and apoptosis, as well as mice xenograft model. In conclusion, our results suggest that the double-negative feedback loop between E2F3b and miR-200b regulates docetaxel chemosensitivity of human LAD cells mainly through cell proliferation, cell cycle distribution and apoptosis.

MiRNAs and E2F3: a complex network of reciprocal regulations in human cancers

E2F transcription factor 3 (E2F3) is oncogenic in tumorigenesis. Alterations in E2F3 functions correspond with poor prognosis in various cancers, underscoring their status for the clinical cancer phenotype. Latest reports discovered intricate networks between microRNAs (miRNAs) and E2F3 in regulating the balance of these events, including proliferation, apoptosis, metastasis, as well as drug resistance. miRNAs are non-coding small RNAs which negatively regulate gene expressions post-transcriptionally mainly through 3′-UTR binding of target mRNAs. Increasing evidence shows that E2F3 can be activated/inhibited by numerous miRNAs whose dysregulation has been implicated in malignancy. In turn, miRNAs themselves can be transcriptionally regulated by E2F3, thus forming a negative feedback loop. These findings add a new challenging layer of complexity to E2F3 network. Current understanding of the reciprocal link between E2F3 and miRNAs in human cancers were summarized, which could help to develop potential therapeutic strategies.

Downregulation of MiR-31 stimulates expression of LATS2 via the hippo pathway and promotes epithelial-mesenchymal transition in esophageal squamous cell carcinoma

BackgroundDysregulation of miRNAs is associated with cancer development by coordinately suppressing abundant target genes. Emerging evidence indicates that miR-31 plays a dual role in tumorigenicity. However, whether miR-31 plays as an oncogene in esophageal squamous cell carcinoma (ESCC) and the potential target molecules are still unclear. MiR-31 role in ESCC was investigated and an association of the target molecules with EMT was identified in the progression of ESCC.MethodsWestern blot assays and qRT-PCR was performed to detect the protein and mRNA levels. We investigated the role of miR-31 in the regulation of LATS2 expression in ESCC cell lines via functional assays both in vivo and in vitro. The luciferase reporter assays was conducted to confirm LATS2 is a potential target of miR-31. Immunohistochemistry was used to measure LATS2 and TAZ expression in normal and ESCC tissue.ResultsLATS2 is a component of the Hippo tumor-suppressive signaling pathway. Frequent loss of heterozygosity of LATS2 has been reported in esophageal cancer. We analyzed the reciprocal expression regulation of miR-31 and LATS2 and demonstrated that LATS2 expression was elevated by down-regulation of miR-31 at the post-transcriptional level in ESCC. Moreover, miR-31 significantly suppressed the luciferase activity of mRNA combined with the LATS2 3′-UTR, a key molecule in the Hippo pathway. Then, LATS2 consequently promoted the translocation of TAZ, which was examined using immunohistochemistry. Silencing of miR-31 significantly inhibited the cell proliferation, induced apoptosis and decreased the ability of migration/invasion in vitro. LATS2 impedes ESCC cell proliferation and invasion by suppressing miR-31, as well as mice xenograft model in vivo. Meanwhile, the nuclear localization of LATS2 constrained the phosphorylation of TAZ. Then, the expression level of TAZ was notably heightened with a high risk of recurrence compared to that observed in the low-risk patients, as well as, the higher expression associated with a poor survival.ConclusionsOur study demonstrated that overexpression of miR-31 undertook an oncogenic role in ESCC by repressing expression of LATS2 via the Hippo Pathway and activating epithelial-mesenchymal transition. LATS2 and TAZ could be potential novel molecular markers for predicting the risk of recurrence and prognosis of ESCC.

The Emerging Role of Inhibitor of Growth 4 as a Tumor Suppressor in Multiple Human Cancers

Inhibitor of growth 4 (ING4), a member of the conserved ING family, has been identified as an important tumor suppressor since it plays a critical role in the regulation of chromatin modification, cell proliferation, angiogenesis and cell migration. Some observations suggest that ING4 acts as a key regulator of tumorigenesis through modifying gene transcription in part by regulating the transcription factors p53 and NF-kappaB (NF-κB). However, these models have yet to be substantiated by further investigations. Numerous reports describe the reduced expression of ING4 in cancers, and the responsible mechanisms are involved in gene deletion, mutation, transcriptional and post-transcriptional dysregulation. This review aims to summarize the recent published literature that investigates the role of ING4 in regulating tumorigenesis and progression, and explore its potential for cancer treatment.