Lnc RNA H19 is associated with poor prognosis in breast cancer patients and promotes cancer stemness

• Published in: Breast cancer research and treatment 2018-08, Vol.170 (3), p.507-516
• Main Authors: Shima, Hidetaka, Kida, Kumiko, Adachi, Shoko, Yamada, Akimitsu, Sugae, Sadatoshi, Narui, Kazutaka, Miyagi, Yohei, Nishi, Mayuko, Ryo, Akihide, Murata, Soichiro, Taniguchi, Hideki, Ichikawa, Yasushi, Ishikawa, Takashi, Endo, Itaru
• Format: Article
• Language: English
• Subjects: Biomarkers, Tumor; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - mortality; Breast Neoplasms - pathology; Cancer patients; Cancer research; Comparative analysis; DNA microarrays; Female; Gene expression; Gene Expression Profiling; Gene Regulatory Networks; Genes; Genetic aspects; Humans; Immunohistochemistry; Isoenzymes - genetics; Isoenzymes - metabolism; Kaplan-Meier Estimate; Medical prognosis; Medical schools; Medicine; Medicine & Public Health; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Non-coding RNA; Oncology; Phenotypes; Preclinical Study; Prognosis; Retinal Dehydrogenase - genetics; Retinal Dehydrogenase - metabolism; RNA; RNA, Long Noncoding - genetics; RNA, Messenger - genetics; siRNA; Stem cells; Triple Negative Breast Neoplasms - genetics
• ISSN: 0167-6806; 1573-7217
• DOI: 10.1007/s10549-018-4793-z

Purpose Aldehyde dehydrogenase1 (ALDH1) is widely accepted as a stem cell marker for normal breast as well as in breast cancer. Although the clinical impact of ALDH1 was observed in our previous study, we do not know how ALDH1 affects stem cell features resulting in worsening of prognosis in breast cancer. The purpose of this study is to explore ALDH1-related gene and its function on cancer stem cell (CSC). Methods In five cases of ALDH1-positive triple-negative breast cancer, mRNA expression profile was compared between ALDH1-positive and ALDH1-negative cells by Affymetrix microarray analysis after microdissection. Among the genes modulated in ALDH1-positive cells, we focused on H19 , which encodes a long non-coding RNA, in this study. An in-vitro study was conducted with H19 siRNA in HCC1934 and iCSCL10A cell lines. The association of H19 with prognosis was examined in 180 breast cancer cases. Results Network analysis revealed the existence of five genes related with H19 , including miR-103, miR-107, let-7, miR-29b-1 , and Trx. In-vitro analysis showed that suppression of H19 using siRNA reduces sphere formation capacity in both HCC1934 and iCSCL10A cell lines. In clinical studies, H19 expression was associated with hormone negativity, tumor size, and nodal status. Patients with H19 expression had significantly poor disease-free survival (DFS) (26.3 vs. 64.8% at 5 years, p  = 0.001) and overall survival (OS) (28.9 vs. 68.3% at 5 years, p  = 0.004). The effect of H19 expression on prognosis was the most significant in triple-negative breast cancer compared to that in other subtypes (20.0 vs. 65.4% at 5 years DFS, p  = 0.012, 20.0 vs. 69.2% at 5 years OS, p  = 0.016). Conclusion This study indicated that H19 was associated with stem cell phenotype in ALDH1-positive breast cancer. H19 regulates CSC and is associated with poor prognosis in breast cancer patients, particularly in triple-negative subtype.