Abstract
Emerging studies indicated that cancer stem cells represent a subpopulation of cells within the tumor that is responsible for chemotherapeutic resistance. However, the underlying mechanism is still not clarified yet. Here we report that miR-196b-5p is dramatically upregulated in CRC tissues and high expression of miR-196b-5p correlates with poor survival in CRC patients. Moreover, recurrent gains (amplification) contribute to the miR-196b-5p overexpression in CRC tissues. Silencing miR-196b-5p suppresses spheroids formation ability, the fraction of SP cells, expression of stem cell factors and the mitochondrial potential, and enhances the apoptosis induced by 5-fluorouracil in CRC cells; while ectopic expression of miR-196b-5p yields an opposite effect. In addition, downregulation of miR-196b-5p resensitizes CRC cells to 5-fluorouracil in vivo. Our results further demonstrate that miR-196b-5p promotes stemness and chemoresistance of CRC cells to 5-fluorouracil via targeting negative regulators SOCS1 and SOCS3 of STAT3 signaling pathway, giving rise to activation of STAT3 signaling. Interestingly, miR-196b-5p is highly enriched in the serum exosomes of patients with CRC compared to the healthy control subjects. Thus, our results unravel a novel mechanism of miR-196b-5p implicating in the maintenance of stem cell property and chemotherapeutic resistance in CRC, offering a potential rational registry of anti-miR-196b-5p combining with conventional chemotherapy against CRC.
Highlights
CRC (CRC) is one of the most common malignant cancers, as well as the primary causes of cancer-related deaths worldwide [1, 2]
Using the publicly available algorithms TargetScan and miRanda, we found that multiple negative regulators of JAK2/signal transducer and activator of transcription 3 (STAT3) signaling, including SOCS1, SOCS2, Figure 1: miR-196b-5p is upregulated in CRC and correlated with poor prognosis. (A–C) miR-196b-5p expression levels was markedly upregulated in CRC tissues as assessed by analyzing the E-GEOD-10259, E-GEOD-41655 and The Cancer Genome Atlas (TCGA) of CRC miRNA sequencing datasets. (D) Real-time PCR analysis of miR-196b-5p in 11 primary CRC tissues compared with the matched adjacent normal tissues (ANT). (E) Real-time PCR analysis of miR-196b-5p expression in 20 paired collected CRC tissue samples
It has been determined that STAT proteins are persistently phosphorylated on the tyrosine residue in the majority of cancers, STAT3, which are required in several aspects of tumorigenesis, including proliferation, apoptosis, increased resistance to chemotherapeutic agents, cancer stem cell and metastasis, leading to the progression of cancer [14, 29, 30]
Summary
CRC (CRC) is one of the most common malignant cancers, as well as the primary causes of cancer-related deaths worldwide [1, 2]. The primary issues responsible for the failure of chemotherapy in CRC patients are the existence of cancer stem cells (CSCs) that are the minority population of cells characterized by the capabilities of self-renewal, unlimited proliferation and differentiation into the multiple lineages of cancer cells [4, 5]. Solute carrier family 34 (type II sodium/phosphate cotransporter), member 2 (SLC34A2) induced chemoresistance in via SLC34A2-Bmi1-ABCC5 signaling in breast cancer cells [6]; cancer stem cells marker CD133+ contributed to resistance to therapy in hepatocellular carcinoma [7], suggesting that these two cellular processes are intimately linked.
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