Long Non-coding RNA-H19 Promotes Breast Cancer Stem Cell Maintenance

Long non-coding RNA-H19(H19)is encoded by H19 gene,transcribes a 2.3kb non-coding RNA transcript by RNA polymerase II,it is an imprinted oncofetal gene and H19 is only transcripted from the maternally inherited allele,and showed evolutionarily conserved in mammals.Moreover,H19 is the first lncRNA discovered.Recent studies show that H19 is overexpressed in several cancers and metastatic cancers,and is significantly correlated with patient poor prognosis.Therefore,H19 has an important role in cancer progression.Several studies report that many breast cancer patients always follow recurrence and metastasis after conventional chemotherapy and radiotherapy.Hence,the scientists further investigate the tumorigenesis,development and recurrence,and propose that cancer stem cells(CSCs)are the basic causes of cancer recurrence and metastasis.In the decades of research in the past,there is no development in therapy for the treatment of cancer stem cells.Studies have reported that breast cancer stem cells(BCSCs)are a small group of breast cancer cells,which is the main reason for incurable of breast cancer.So far,many studies have highlighted the important roles and mechanism of H19 during the complex process of breast tumorigenesis,and obtain many exciting results.The mechanism by how H19 regulates CSCs remains elusive.The objective of our research was to further determine whether H19 has a potential role for BCSCs maintenance.We also shows that H19 RNA functions as the molecular sponge for let-7,a tumor suppressor microRNA.Thus,H19 promotes tumor progression by sponging let-7 and modulates the stemness of breast cancer cells.Moreover,H19 can regulate the expression of LIN28,and there contain let-7 binding sequences in 3'UTR of LIN28.Finally,we obtained that H19 affects breast cancer initiation and progression by regulating microRNA and tumor pluripotency factors in breast cancer cells.The main results are as follows:1.Firstly,we verified that the expression of H19 in breast tumor tissues is increased,then we enriched BCSCs by using flow cytometry sorting assay,and verified H19 expression level.We showed that H19 is overexpressed in breast cancer tissues and BCSCs2.Next,we abnormally expressed H19 in breast cancer cells(overexpression or silencing),and found that ectopic overexpression of H19 promotes breast cancer cells stemness.Conversely,silencing of H19 of breast cancer cells represses these BCSCs properties.3.Furthermore,we found that H19 could regulate the expression level of CSCs biomarker LIN28 in breast cancer cells.And the gain of LIN28 expression in breast cancer cells can feedback to reverse the H19 loss-mediated suppression of BCSC properties.Appropriately,through the analysis of the patients with breast cancer data showed that H19 and LIN28 expression exhibits strong correlations in primary breast carcinomas.4.Mechanistically,We extracted several information from previous studies.We found that H19 modulated the expression of let-7,in addition,let-7 affected LIN28 expression level.Thus,we revealed that H19 could function as a competing endogenous RNA(ceRNA)to sponge microRNA let-7 in breast cancer,and leading to an increasing expression of let-7 targets,and the expression level of let-7 did not change.Thus,H19 only affect the bioavailability rather than expression.Otherwise,functional inhibition of let-7 could not suppress the expression of LIN28 in the breast cancer cells,so the expression of LIN28 increased.LIN28 is the core pluripotency factor,which is enriched in BCSCs populations and breast patient samples.Conclusion: These findings reveal the previously unknown mechanism that lncRNA H19,microRNA let-7 and CSCs biomarker LIN28 form a regulate pathway,which has a critical role in the maintenance of BCSCs.Consequently,disrupting this pathway provides a novel therapeutic strategy for breast cancer.