Small activating RNA restores the activity of the tumor suppressor HIC-1 on breast cancer.
HIC-1 is a gene that is hypermethylated in cancer, and commonly downregulated in human breast cancer. However, the precise mechanisms and molecular pathways regulated by HIC-1 remain unclear. We assessed HIC-1 expression on a tissue microarray containing 80 cases of breast cancer. We also analyzed its biological function by restoring HIC-1 expression using 5-aza-2' deoxycytidine (5-CdR) and small-activating RNAs for the reversal of HIC-1 tumor suppressive effects on MCF-7 and MDA-MB-231 cell lines. An Agilent Q44h global expressing microarray was probed after restoring the expression of HIC-1. Data demonstrated that HIC-1 expression was reduced significantly in breast cancer tissues. HIC-1 immunohistochemistry resulted in mean staining scores in cancer tissue and normal ductal epithelia of 3.54 and 8.2, respectively (p<0.01). 5-CdR partially reversed HIC-1 expression, and modulated cell growth and apoptosis. dsHIC1-2998, an saRNA, showed activating efficacy in breast cancer cells. A group of differentially expressed genes were characterized by cDNA microarray. Upon saRNA treatment, genes upregulated included those involved in immune activation, cell cycle interference, the induction of apoptosis, anti-metastasis, and cell differentiation. Downregulated genes included oncogenes and those that play roles in cell invasion, cell growth, and cell division. Our findings may provide valuable resources not only for gene functional studies, but also for potential clinical applications to develop novel drug targets.
Department of Surgery, The Ninth People's Hospital of Shanghai Jiao Tong University, School of Medicine, Shanghai, China.
Feng
F
Zhao
Department of Surgery, Shanghai Ruijin Hospital of Shanghai Jiao Tong University, School of Medicine, Shanghai, China.
Shengli
S
Pan
Department of Surgery, The Ninth People's Hospital of Shanghai Jiao Tong University, School of Medicine, Shanghai, China.
Yan
Y
Gu
Department of Surgery, The Ninth People's Hospital of Shanghai Jiao Tong University, School of Medicine, Shanghai, China.
Shanyu
S
Guo
Department of Surgery, The Ninth People's Hospital of Shanghai Jiao Tong University, School of Medicine, Shanghai, China.
Qiancheng
Q
Dai
Department of Surgery, Shanghai Ruijin Hospital of Shanghai Jiao Tong University, School of Medicine, Shanghai, China.
Yingyan
Y
Yu
Department of Surgery, The Ninth People's Hospital of Shanghai Jiao Tong University, School of Medicine, Shanghai, China.
Wei
W
Zhang
D000328:Adult; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000077209:Decitabine; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D012313:RNA / Q000378:metabolism*; D046888:Tissue Array Analysis; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects
C499808:HIC1 protein, human; D051741:Kruppel-Like Transcription Factors; D012313:RNA; D000077209:Decitabine; D001374:Azacitidine