MicroRNA-33a-mediated downregulation of Pim-3 kinase expression renders human pancreatic cancer cells sensitivity to gemcitabine

Liang, Chen; Lei, Yu; Guo, Xusheng; Sun, Meng; Wang, Zhen; Song, Yanyu; Ni, Quan Xing; Li, Hong Yu; Mukaida, Naofumi; Li, Ying Yi

doi:10.18632/oncotarget.3885

Cited by 61 publications

(57 citation statements)

References 49 publications

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“…It has been indicated that miRNAs may have oncogenic or tumor-suppressive effects in human malignancies and may also serve as promising biomarkers and therapeutic targets in the diagnosis and treatment of cancer (3,29). miR-33a is an established regulator of glucose and cholesterol metabolism (14,30) and has been demonstrated to be an active regulator in the pathogenesis of various human cancers, including pancreatic cancer (15,16), lung cancer (17), glioma (18), osteosarcoma (31) and colon cancer (32). In the present study, significant overexpression of miR-33a was confirmed in HCC tissues.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to its functional roles in metabolism, miR-33a has been implicated in a number of human cancers. In pancreatic ductal adenocarcinoma, it has been observed that miR-33a exerts tumor suppressive effects, by modulating the growth, apoptosis, epithelial-to-mesenchymal transition and chemoresistance of pancreatic cancer cells (15,16). Similarly, a previous study in lung cancer demonstrated that miR-33a had inhibitory effects on the metastasis of cancer cells towards bone tissue (17).…”

Section: Introductionmentioning

confidence: 90%

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MicroRNA-33a promotes cell proliferation and inhibits apoptosis by targeting PPARα in human hepatocellular carcinoma

Chang

Zhang

Xian

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. ) is dysregulated in a number of human cancers, where it functions as an oncogenic miRNA. However, the clinical significance of miR-33a and its underlying molecular pathways regarding the progression of hepatocellular carcinoma (HCC) are currently unknown. In the present study, it was observed that the level of miR-33a expression was significantly increased in HCC tissues, relative to adjacent non-tumor tissues. Increased miR-33a expression was significantly correlated with poor prognostic features of HCC, including larger tumor size, higher Edmondson-Steiner grading and higher tumor-node-metastasis tumor stage. Furthermore, high levels of miR-33a expression were associated with decreases in the 5-year overall survival rate and recurrence-free survival of patients with HCC. In addition, functional experiments indicated that overexpression of miR-33a led to increased proliferation and reduced apoptosis of the HCC cell line Huh7, while knockdown of miR-33a decreased proliferation and induced apoptosis in the HCC cell line HepG2. Furthermore, peroxisome proliferator activated receptor alpha (PPARα) was identified as a direct target of miR-33a in HCC. Upregulation of miR-33a was found to reduce the levels of PPARα expression in Huh7 cells, while inhibition of miR-33a lead to a downregulation in PPARα expression in HepG2 cells. Collectively, these results suggest that miR-33a regulates the proliferation and apoptosis of HCC cells, and is a potential prognostic marker of HCC.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 90%

MicroRNA-33a promotes cell proliferation and inhibits apoptosis by targeting PPARα in human hepatocellular carcinoma

Chang

Zhang

Xian

et al. 2017

Experimental and Therapeutic Medicine

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“…miRs regulate the gene expression in the majority of biological processes in the cell, and therefore have been hypothesized to serve an important role in the chemoresistance to standard treatment regimens in pancreatic cancer. Numerous studies demonstrated that miRs are differentially expressed in a variety of types of cancer (44)(45)(46)(47)(48)(49)(50). A study examining the miR profile of gemcitabine-sensitive and resistant pancreatic cancer cell lines reported the presence of 33 differentially regulated miRs (44).…”

Section: Pancreatic Stellate Cells (Pscs)mentioning

confidence: 99%

“…Of these miRs, miR-497 was the most downregulated gene, and its upregulation resulted in the sensitization of the pancreatic cancer cells to gemcitabine and erlotinib (44). miR-33a overexpression has been demonstrated to sensitize pancreatic cancer cells to gemcitabine and inhibit tumor growth through the suppression of Pim-3 kinase expression (45). Incidentally, miR-33a was also reported to be downregulated in gemcitabine-resistant cells (44).…”

Section: Pancreatic Stellate Cells (Pscs)mentioning

confidence: 99%

Chemoresistance in pancreatic cancer: Emerging concepts

Gnanamony

Gondi

2017

Oncology Letters

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Abstract. Pancreatic cancer is one of the most lethal types of cancer in the world. The incidence of pancreatic cancer increases each year with no significant decrease in mortality. Pancreatic cancer is a complex disease, and this complexity is partly attributed to late diagnosis, an aggressive phenotype, environmental factors and lack of effective treatment options. Surgical resection followed by adjuvant chemotherapy is the treatment of choice for early stage cancer, whereas gemcitabine is the standard first line therapy for patients with advanced stage disease. Treatment regimens comprising folinic acid, 5-fluorouracil, irinotecan, oxaliplatin and nab-paclitaxel have demonstrated modest effects in improving median survival rates. A number of other chemotherapeutics are currently undergoing clinical trials as components of combination therapies with gemcitabine. An increasing number of novel molecular targets and cellular pathways are being identified, which highlights the complexity of this disease. The development of chemoresistance to gemcitabine is multifactorial and there exists an interplay between pancreatic cancer cells, the tumor microenvironment and cancer stem cells. These components appear to be governed by a complex network of non-coding RNAs such as micro RNAs and long non-coding RNAs. In the present study, studies describing previous research on the understanding of the factors associated with the development of chemoresistance to gemcitabine in pancreatic cancer are reviewed. A comprehensive understanding of the multiple pathways of chemoresistance is key to develop next generation therapeutics to pancreatic cancer.

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“…On the other hand, miR-21 is upregulated in pancreatic cancer cells, and it has several targets including phosphatase and tensin homolog, programmed cell death protein 4, and tropomyosin alpha-1 chain, which leads to the inhibition of apoptosis [12]. Studies also showed that miR-33a-mediated downregulation of Pim-3 kinase expression is associated with the sensitivity of human pancreatic cancer cells to gemcitabine [13]. The tumor suppressive role of miR-125a has been found in many types of cancers, including liver cancer [14], colon cancer [15], and breast cancer [16].…”

Section: Introductionmentioning

confidence: 99%

MiR-125a regulates chemo-sensitivity to gemcitabine in human pancreatic cancer cells through targeting A20

Yao

Wang

et al. 2016

ABBS

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly human malignant diseases and the sixth leading cause of cancer-related deaths in China. Gemcitabine is the only first-line chemotherapeutic agent used for the palliative treatment of patients with PDAC, but chemo-resistance limits their efficacy. Here, we showed that miR-125a was up-regulated in chemo-resistant SW1990GZ cells when compared with SW1990 cells. Over-expression of miR-125a increased the chemoresistance to gemcitabine in SW1990 cells, while down-regulation of miR-125a in SW1990GZ cells increased chemo-sensitivity to gemcitabine. By using bioinformatics analysis tool (Targetscan), the 3′ untranslated region (3′UTR) of A20 gene was found to be a target of miR-125a. Luciferase reporter assay further confirmed that A20 3′UTR is a direct target of miR-125a. Over-expression of A20 in SW1990 cells increased chemo-sensitivity to gemcitabine, while knockdown of A20 in SW1990 cells promoted the chemo-resistance to gemcitabine. Finally, the expression level of miR-125a in pancreatic cancer tissues from chemo-sensitive patients was significantly lower than that from chemo-resistant patients, and was inversely correlated with the A20 mRNA levels. In conclusion, our results suggest that miR-125a promotes chemo-resistance to gemcitabine in pancreatic cells through targeting A20, which may provide novel therapeutic targets or molecular biomarkers for cancer therapy and improve tumor diagnosis or predictions of therapeutic responses.

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MicroRNA-33a-mediated downregulation of Pim-3 kinase expression renders human pancreatic cancer cells sensitivity to gemcitabine

Cited by 61 publications

References 49 publications

MicroRNA-33a promotes cell proliferation and inhibits apoptosis by targeting PPARα in human hepatocellular carcinoma

MicroRNA-33a promotes cell proliferation and inhibits apoptosis by targeting PPARα in human hepatocellular carcinoma

Chemoresistance in pancreatic cancer: Emerging concepts

MiR-125a regulates chemo-sensitivity to gemcitabine in human pancreatic cancer cells through targeting A20

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