OCRF Grantee Lin Zhang, MD
Research has provided strong support for the ovarian cancer stem cell hypothesis, which proposes that a rare subpopulation of tumor cells—cancer stem cells– have the unique ability to initiate and perpetuate tumor growth. The studies in Dr. Lin Zhang’s laboratory, which were supported by an OCRF Liz Tilberis award, have provided new evidence indicating that the miRNA (a short ribonucleic acid) let-7 regulates cancer stem cell populations in ovarian cancer. Based on this finding, a new therapeutic strategy will be designed and further tested in preclinical animal models of ovarian cancer. The work was recently published in Cancer Research, a journal of the American Association for Cancer Research. Meanwhile, two related papers of this project have also been published recently in the Journal of Biological Chemistry and PLoS ONE.
Zhang and colleagues hypothesize that the tumor suppressor microRNA let-7 regulates the differentiation of cancer stem cells, and that restoration of miRNA expression will significantly suppress the self-renewal ability, promoting cancer stem cells to differentiate. Research on stem cell cells indicates that cancer stem cells may arise through a “reprogramming” mechanism. LIN28, one of reprogramming factors, is very restricted in its expression; it is found only in embryonic stem cells, developing tissues, and tumors. In ovarian tumors, they have shown that LIN28/LIN28B is upregulated and functions as an oncogene, promoting malignant transformation and tumor progression. In addition, LIN28 is positively correlated with the percentage of cancer stem cells in ovarian cancer, suggesting that LIN28 may play a role in regulation of ovarian cancer stem cells.
In further functional studies they have shown that LIN28 indeed functionally maintains this cell population. Reactivated reprogramming factors such as LIN28 may promote the conversion of epithelial cells to a more undifferentiated stage, and furthermore maintain a small subpopulation of tumor cells in this stem cell-like stage. Meanwhile, using a combinatorial approach, they successfully identified four miRNA families, which regulate LIN28 expression in embryonic stem cells and cancer cells. Given that LIN28 can act as a reprogramming factor together with OCT4, SOX2 and NANOG to reprogram somatic cells to stem cells, co-transfection of these LIN28 regulatory miRNA inhibitors prevent somatic cell reprogramming to stem cells, and it also provides a potential to develop new therapeutic strategies for ovarian cancer treatment.
This study provided critical insights into the function of miRNAs in ovarian cancer pathogenesis and delineates the rationale for their therapeutic targeting. Based on this discovery, the translational researchers at the Penn Ovarian Cancer Research Center are commencing a pre-clinical trial in ovarian cancer animal model as well as a phase 0/I clinical trial in ovarian cancer patients.
Yang X, Lin X, Zhong X, Kaur S, Li X, Liang S, Lassus H, Wang L, Katsaros D, Montone K, Zhao X, Zhang Y, Bützow R, Coukos G, Zhang L: Double negative feedback loop between reprogramming factor LIN28 and microRNA let-7 regulates aldehyde dehydrogenase 1-positive cancer stem cells. Cancer Research, 2010, Nov 2. [Epub ahead of print]
Zhong X, Li N, Liang S, Huang Q, Coukos G, Zhang L: Identification of microRNAs regulating reprogramming factor LIN28 in embryonic stem cells and cancer cells. Journal of Biological Chemistry, 2010, Oct 14. [Epub ahead of print].
Deng S, Yang X, Lassus H, Liang S, Kaur S, Ye Q, Li C, Wang LP, Roby KF, Orsulic S, Connolly DC, Zhang Y, Montone K, Bützow R, Coukos G, Zhang L: Distinct expression levels and patterns of stem cell marker, aldehyde dehydrogenase isoform 1 (ALDH1), in human epithelial cancers. PLoS ONE 5(4):e10277, Apr, 2010.