MicroRNAs overexpressed in ovarian ALDH1-positive cells are associated with chemoresistance

Abstract

BackgroundOvarian carcinoma is the leading cause of cancer death worldwide among gynecological malignancies, and the majority of cases are related with recurrence and chemoresistance. Cancer stem cells (CSCs) are believed to be one of the causes of recurrent or chemoresistant ovarian cancer, and microRNAs are regulatory molecules newly implicated to control a variety of cellular processes, including CSCs. Therefore, we identified ovarian CSC-specific microRNAs and investigated their clinicopathological implication in ovarian carcinomas.MethodsWe isolated ALDH1 (+) cell population using the Aldefluor assay, and examined the differential expression pattern of miRNAs between ALDH1 (+) and ALDH1 (−) cells using a high-throughput microRNA microarray. We further investigated the expression patterns of differentially expressed miRNAs in human ovarian cancer samples using the real-time reverse transcription-polymerase chain reaction and analyzed their clinical impact in patients with ovarian cancer.ResultsWe found that high ALDH1 expression was associated with chemoresistance in in vitro and ex vivo samples (p = 0.024). We identified six miRNAs, including miR-23b, miR-27a, miR-27b, miR-346, miR-424, and miR-503, overexpressed in ALDH1 (+) cells, and they were significantly upregulated in chemoresistant ovarian cancer cells (1.4 ~ 3.5-fold) and tumor samples (2.8 ~ 5.5-fold) compared with chemosensitive group. Upregulation of ALDH1 (p = 0.019) and miR-503 (p = 0.033) correlated with high clinical stage, and upregulation of miR-27a was related with distant metastasis (p = 0.046) in patients with ovarian cancer.ConclusionOur findings indicate that ALDH1 is a useful marker for enriching ovarian CSCs, and high expression of ALDH1 and its related miRNAs, particularly miR-23b, miR-27b, miR-424, and miR-503, are significantly implicated in chemoresistance and tumor progression in ovarian cancer.

Establishment and Characterization of an In Vitro Model of Ovarian Cancer Stem-like Cells with an Enhanced Proliferative Capacity

“…Functional analyses by gene knockdown and a chemical inhibitor revealed that ALDH and SOX2 are essential for the proliferation of ovarian CSCs. Of note, both ALDH1A and SOX2 expression contribute to chemo-resistance of ovarian cancer cell lines (35,(43)(44)(45). Therefore, SOX2 and ALDH may mediate its capability to confer chemo-resistance to ovarian CSCs as well as stem cell-related features.…”

Genomewide Study of Salivary MicroRNAs for Detection of Oral Cancer

“…In the in vivo model, they found that engineered knockdown of miRNA27b substantially repressed breast cancer growth in mice and increased miRNA27b levels correlate with poor treatment outcomes. Park et al (2013) showed that miRNA-27b is overexpressed in ovarian ALDH1-positive cells and associated with chemoresistance and tumor progression.…”

Non-Coding RNAs Mediate Chemotherapy Resistance in Ovarian Cancer

“…Six miRNAs, including miR-23b, miR-27a, miR-27b, miR-346, miR-424, and miR-503, were overexpressed in ovarian ALDH1-positive cells, and they were significantly upregulated in chemoresistant ovarian cancer cells and tumor samples compared with chemosensitive group. High ALDH1 expression was associated with chemoresistance in in vitro and ex vivo samples [26]. Besides, miR-200 family [27][28][29][30], miR-199/214 cluster [31][32][33][34][35], miR-31 [36] et al, are also reported to be connected with chemotherapy resistance, including cisplatin and pactitaxel (Table 1).…”