Specific-detection of clinical samples, systematic functional investigations, and transcriptome analysis reveals that splice variant MUC4/Y contributes to the malignant progression of pancreatic cancer by triggering malignancy-related positive feedback l
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  • 作者：Yi Zhu (1) (2)
    Jing-Jing Zhang (1) (2)
    Kun-Ling Xie (1)
    Jie Tang (1)
    Wen-Biao Liang (3)
    Rong Zhu (4)
    Yan Zhu (5)
    Bin Wang (6)
    Jin-Qiu Tao (1)
    Xiao-Fei Zhi (1)
    Zheng Li (1)
    Wen-Tao Gao (1) (2)
    Kui-Rong Jiang (1) (2)
    Yi Miao (1) (2)
    Ze-Kuan Xu (1) (2)

    1. Department of General Surgery     ; First Affiliated Hospital ; Nanjing Medical University ; 300 Guangzhou Road ; Nanjing ; 210029 ; Jiangsu Province ; People鈥檚 Republic of China
    2. Jiangsu Province Academy of Clinical Medicine     ; Institute of Tumor Biology ; Nanjing ; 210029 ; People鈥檚 Republic of China
    3. Jiangsu Province Blood Center     ; Nanjing ; 210042 ; People鈥檚 Republic of China
    4. Department of Pathology     ; Shanghai Medical College ; Fudan University ; Shanghai ; 200032 ; People鈥檚 Republic of China
    5. Department of Pathology     ; First Affiliated Hospital ; Nanjing Medical University ; Nanjing ; 210029 ; People鈥檚 Republic of China
    6. Department of General Surgery     ; the First Affiliated Hospital of Soochow University ; Suzhou ; 215006 ; People鈥檚 Republic of China
  • 关键词：MUC4/Y ; Alternative splicing ; Pancreatic neoplasms ; Cell movement ; Angiogenesis ; Neoplasm metastasis ; Gene expression regulation ; Signal transduction
  • 刊名：Journal of Translational Medicine
  • 出版年：2014
  • 出版时间：December 2014
  • 年：2014
  • 卷：12
  • 期：1
  • 全文大小：7,838 KB
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  • 刊物主题：Biomedicine general; Medicine/Public Health, general;
  • 出版者：BioMed Central
  • ISSN：1479-5876
文摘
Background MUC4 plays important roles in the malignant progression of human pancreatic cancer. But the huge length of MUC4 gene fragment restricts its functional and mechanism research. As one of its splice variants, MUC4/Y with coding sequence is most similar to that of the full-length MUC4 (FL-MUC4), together with alternative splicing of the MUC4 transcript has been observed in pancreatic carcinomas but not in normal pancreas. So we speculated that MUC4/Y might be involved in malignant progression similarly to FL-MUC4, and as a research model of MUC4 in pancreatic cancer. The conjecture was confirmed in the present study. Methods MUC4/Y expression was detected by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) using gene-specific probe in the clinic samples. The effects of MUC4/Y were observed by serial in vitro and in vivo experiments based on stable over-expressed cell model. The underlying mechanisms were investigated by sequence-based transcriptome analysis and verified by qRT-PCR, Western blot and enzyme-linked immunosorbent assays. Results The detection of clinical samples indicates that MUC4/Y is significantly positive-correlated with tumor invasion and distant metastases. Based on stable forced-expressed pancreatic cancer PANC-1 cell model, functional studies show that MUC4/Y enhances malignant activity in vitro and in vivo, including proliferation under low-nutritional-pressure, resistance to apoptosis, motility, invasiveness, angiogenesis, and distant metastasis. Mechanism studies indicate the novel finding that MUC4/Y triggers malignancy-related positive feedback loops for concomitantly up-regulating the expression of survival factors to resist adverse microenvironment and increasing the expression of an array of cytokines and adhesion molecules to affect the tumor milieu. Conclusions In light of the enormity of the potential regulatory circuitry in cancer afforded by MUC4 and/or MUC4/Y, repressing MUC4 transcription, inhibiting post-transcriptional regulation, including alternative splicing, or blocking various pathways simultaneously may be helpful for controlling malignant progression. MUC4/Y- expression model is proven to a valuable tool for the further dissection of MUC4-mediated functions and mechanisms.

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