MicroRNA-128 suppresses paclitaxel-resistant lung cancer by inhibiting MUC1-C and BMI-1 in cancer stem cells

Abstract

The existence of cancer stem cells (CSCs) is the main reason for failure of cancer treatment caused by drug resistance. Therefore, eradicating cancers by targeting CSCs remains a significant challenge. In the present study, because of the important role of BMI-1 proto-oncogene, polycomb ring finger (BMI-1) and C-terminal Mucin1 (MUC1-C) in tumor growth and maintenance of CSCs, we aimed to confirm that microRNA miR-128, as an inhibitor of BMI-1 and MUC1-C, could effectively suppress paclitaxel (PTX)-resistant lung cancer stem cells. We showed that CSCs have significantly higher expression levels of BMI-1, MUC1-C, stemness proteins, signaling factors, and higher malignancy compared with normal tumor cells. After transfection with miR-128, the BMI-1 and MUC1-C levels in CSCs were suppressed. When miR-128 was stably expressed in PTX-resistant lung cancer stem cells, the cells showed decreased proliferation, metastasis, self-renewal, migration, invasive ability, clonogenicity, and tumorigenicity in vitro and in vivo and increased apoptosis compared with miR-NC (negative control) CSCs. Furthermore, miR-128 effectively decreased the levels of β-catenin and intracellular signaling pathway-related factors in CSCs. MiR-128 also decreased the luciferase activity of MUC1 reporter constructs and reduced the levels of transmembrane MUC1-C and BMI-1. These results suggested miR-128 as an attractive therapeutic strategy for PTX-resistant lung cancer via inhibition of BMI-1 and MUC1-C.

microRNA: The Impact on Cancer Stemness and Therapeutic Resistance

“…Due to the suppression of MUC1-C and BMI-1, the MEK/ERK, PI3K/Akt and Wingless (Wnt)/β-catenin pathways are downregulated, leading to a decrease of the CSC population and impaired chemoresistance to PTX. In short, miR-128 is one of the potential targets for lung cancer treatment [32].…”

Melatonin disturbs SUMOylation‐mediated crosstalk between c‐Myc and nestin via MT1 activation and promotes the sensitivity of paclitaxel in brain cancer stem cells

“…Although paclitaxel, so‐called taxol, has been used for chemotherapy in several cancers including ovarian cancer, breast cancer, lung cancer, Kaposi sarcoma, cervical cancer, and pancreatic cancer and cancer stem cells, its resistance in stem cells and side effects are still hot issues for effective cancer therapy. Hence, new combination therapy with paclitaxel is attractive to overcome its resistance and side effects.…”

MicroRNA‐128/homeobox B8 axis regulates ovarian cancer cell progression

“…Paclitaxel is a natural anti‐tumour agent that widely used for the treatment of a variety of tumours, including ovarian cancer . Koh et al reported that miR‐128 suppressed cell proliferation, metastasis, self‐renewal, migration and invasive ability of paclitaxel‐resistant lung cancer stem cells via inhibiting BMI‐1 proto‐oncogene, polycomb ring finger (BMI‐1) and C‐terminal Mucin1 (MUC1‐C). A previous study showed that miR‐128 level was decreased in cisplatin‐resistant epithelial ovarian cancer SKOV‐3/CP cells compared with that in parental SKOV‐3 cells, and miR‐128 overexpression suppressed cisplatin resistance in SKOV‐3/CP cells .…”

“…Accumulating evidence has proven that miRNAs regulate thousands of cancer‐associated genes, thereby participating in cancer progression and suppression . miRNA‐128 (miR‐128) has been found to be involved in various cancers, such as gastric cancer, colorectal cancer, osteosarcoma, breast cancer and lung cancer . Recently, miR‐128 was found to be dysregulated in ovarian cancer .…”