Kuan-Chun Huang1, Junzheng Yang1, Michelle C Ng2, Shu-Kay Ng3, William R Welch2, Michael G Muto1, Ross S Berkowitz1, Shu-Wing Ng4. 1. Laboratory of Gynecologic Oncology, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Boston, MA 02115, USA. 2. Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. 3. School of Medicine and Menzies Health Institute Queensland, Griffith University, Meadowbrook, Australia. 4. Laboratory of Gynecologic Oncology, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Boston, MA 02115, USA. Electronic address: sng@partners.org.
Abstract
BACKGROUND: The development of intrinsic and acquired resistance to antineoplastic agents is a major obstacle to successful chemotherapy in ovarian cancers. Identification and characterisation of chemoresponse-associated biomarkers are of paramount importance for novel therapeutic development. METHODS: Global RNA expression profiles were obtained by high-throughput microarray analysis. Cell cycle, proliferation rate, and paclitaxel sensitivity of ovarian cancer cells harbouring cyclin A1-inducible expression construct were compared with and without tetracycline induction, as well as when the cyclin A1 expression was suppressed by short inhibiting RNA (siRNA). Cellular senescence was evaluated by β-galactosidase activity staining. RESULTS: Global RNA expression profiling and subsequent correlation studies of gene expression level and drug response has identified that elevated expression of cyclin A1 (CCNA1) was significantly associated with cellular resistance to paclitaxel, doxorubicin and 5-fluorouracil. The role of cyclin A1 in paclitaxel resistance was confirmed in ovarian cancer cells that harbour an inducible cyclin A1 expression construct, which showed reduced paclitaxel-mediated growth inhibition and apoptosis when cyclin A1 expression was induced, whereas downregulation of cyclin A1 expression in the same cell lines using cyclin A1-specific siRNAs sensitised the cells to paclitaxel toxicity. However, ovarian cancer cells with ectopic expression of cyclin A1 demonstrated slowdown of proliferation and senescence-associated β-galactosidase activity. CONCLUSIONS: Our profiling and correlation studies have identified cyclin A1 as one chemoresistance-associated biomarker in ovarian cancer. The results of the characterisation studies suggest that cyclin A1 functions as an oncogene that controls proliferative and survival activities in tumourigenesis and chemoresistance of ovarian cancer.
BACKGROUND: The development of intrinsic and acquired resistance to antineoplastic agents is a major obstacle to successful chemotherapy in ovarian cancers. Identification and characterisation of chemoresponse-associated biomarkers are of paramount importance for novel therapeutic development. METHODS: Global RNA expression profiles were obtained by high-throughput microarray analysis. Cell cycle, proliferation rate, and paclitaxel sensitivity of ovarian cancer cells harbouring cyclin A1-inducible expression construct were compared with and without tetracycline induction, as well as when the cyclin A1 expression was suppressed by short inhibiting RNA (siRNA). Cellular senescence was evaluated by β-galactosidase activity staining. RESULTS: Global RNA expression profiling and subsequent correlation studies of gene expression level and drug response has identified that elevated expression of cyclin A1 (CCNA1) was significantly associated with cellular resistance to paclitaxel, doxorubicin and 5-fluorouracil. The role of cyclin A1 in paclitaxel resistance was confirmed in ovarian cancer cells that harbour an inducible cyclin A1 expression construct, which showed reduced paclitaxel-mediated growth inhibition and apoptosis when cyclin A1 expression was induced, whereas downregulation of cyclin A1 expression in the same cell lines using cyclin A1-specific siRNAs sensitised the cells to paclitaxeltoxicity. However, ovarian cancer cells with ectopic expression of cyclin A1 demonstrated slowdown of proliferation and senescence-associated β-galactosidase activity. CONCLUSIONS: Our profiling and correlation studies have identified cyclin A1 as one chemoresistance-associated biomarker in ovarian cancer. The results of the characterisation studies suggest that cyclin A1 functions as an oncogene that controls proliferative and survival activities in tumourigenesis and chemoresistance of ovarian cancer.
Authors: C Canino; F Mori; A Cambria; A Diamantini; S Germoni; G Alessandrini; G Borsellino; R Galati; L Battistini; R Blandino; F Facciolo; G Citro; S Strano; P Muti; G Blandino; M Cioce Journal: Oncogene Date: 2011-10-24 Impact factor: 9.867
Authors: D Kitsberg; E Formstecher; M Fauquet; M Kubes; J Cordier; B Canton; G Pan; M Rolli; J Glowinski; H Chneiweiss Journal: J Neurosci Date: 1999-10-01 Impact factor: 6.167
Authors: Masashi Narita; Masako Narita; Valery Krizhanovsky; Sabrina Nuñez; Agustin Chicas; Stephen A Hearn; Michael P Myers; Scott W Lowe Journal: Cell Date: 2006-08-11 Impact factor: 41.582
Authors: C Liao; X Y Wang; H Q Wei; S Q Li; T Merghoub; P P Pandolfi; D J Wolgemuth Journal: Proc Natl Acad Sci U S A Date: 2001-05-29 Impact factor: 11.205
Authors: Kuan-Chun Huang; Pulivarthi H Rao; Ching C Lau; Edith Heard; Shu-Kay Ng; Carolyn Brown; Samuel C Mok; Ross S Berkowitz; Shu-Wing Ng Journal: Mol Cancer Ther Date: 2002-08 Impact factor: 6.261
Authors: Shixiang Sun; Ryan R White; Kathleen E Fischer; Zhengdong Zhang; Steven N Austad; Jan Vijg Journal: Geroscience Date: 2020-06-23 Impact factor: 7.713
Authors: Jing Jing Liu; Jung Yoon Ho; Hye Won Lee; Min Wha Baik; Oyoung Kim; Youn Jin Choi; Soo Young Hur Journal: Int J Mol Sci Date: 2019-07-10 Impact factor: 5.923
Authors: Karol Mierzejewski; Łukasz Paukszto; Aleksandra Kurzyńska; Zuzanna Kunicka; Jan P Jastrzębski; Karol G Makowczenko; Monika Golubska; Iwona Bogacka Journal: Sci Rep Date: 2022-03-07 Impact factor: 4.379