The miR-200 family controls beta-tubulin III expression and is associated with paclitaxel-based treatment response and progression-free survival in ovarian cancer patients.
Ovarian cancer remains one of the leading causes of cancer deaths. Thus, new biomarkers predictive of response to the standard paclitaxel-carboplatin treatment are needed to improve chemotherapy strategies. MicroRNAs have the potential to modify drug outcomes. Based on this, we have demonstrated in this study that patients with a high expression of the miR-200 family show low levels of β-tubulin class III in ovarian carcinoma. In addition, we have established the clinical relevance of these microRNAs for ovarian cancer patients' treatment response and survival. In a well-characterized series of 72 ovarian carcinomas, the expressions of miR-141, miR-200a, miR-200b, miR-200c, and miR-429 were quantified by quantitative reverse transcription-PCR, and the protein content of β-tubulin isotypes I, II, and III was determined by immunohistochemistry. The relationship between these microRNAs, β-tubulin expression, response to paclitaxel-based treatment, progression-free survival (PFS) and overall survival was determined. While isotype I had constant high levels, protein expression of β-tubulins II and III was mutually exclusive. Low tumoral miR-200 expression was significantly associated with high β-tubulin III protein content (P values range, 0.047-<0.0001), and patients without complete response (CR) had lower miR-200c levels than patients with CR (hazard ratio (HR)=1.43, 95% confidence interval (CI)=1.02-1.99, P=0.037, multivariate analysis). Additionally, low miR-200 family expression had a trend toward poor PFS (HR>2.0, P values 0.051, 0.054, and 0.079 for miR-200c, miR-141, and miR-429 respectively, multivariate analysis). In conclusion, miR-200 family members affect the final β-tubulin III protein content of ovarian carcinomas. Furthermore, these microRNAs might constitute the biomarkers of response to paclitaxel-based treatments and relapse/progression of advanced stage ovarian carcinoma patients.
Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Research Center, Melchor Fernández Almagro 3, 28029 Madrid, Spain.
Susanna
S
Leskelä
Luis J
LJ
Leandro-García
Marta
M
Mendiola
Jorge
J
Barriuso
Lucía
L
Inglada-Pérez
Iván
I
Muñoz
Beatriz
B
Martínez-Delgado
Andrés
A
Redondo
Javier
J
de Santiago
Mercedes
M
Robledo
David
D
Hardisson
Cristina
C
Rodríguez-Antona
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D054316:Biomarkers, Pharmacological / Q000032:analysis / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D002277:Carcinoma / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000032:analysis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008875:Middle Aged; D005810:Multigene Family / Q000235:genetics / Q000502:physiology; D010051:Ovarian Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics; D017239:Paclitaxel / Q000008:administration & dosage*; D011379:Prognosis; D012189:Retrospective Studies; D014404:Tubulin / Q000235:genetics* / Q000378:metabolism
D054316:Biomarkers, Pharmacological; D014408:Biomarkers, Tumor; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D014404:Tubulin; D017239:Paclitaxel