Docetaxel-resistant triple-negative breast cancer cell-derived exosomal lncRNA LINC00667 reduces the chemosensitivity of breast cancer cells to docetaxel <em>via</em> targeting miR-200b-3p/Bcl-2 axis

Abstract

Development of docetaxel (TXT) resistance is a major obstacle for triple-negative breast cancer (TNBC) treatment. Additionally, chemoresistant cell-derived exosomes were able to change the chemo-response of chemosensitive recipient cells via transportation of lncRNAs. It has been shown that lncRNA LINC00667 level was significantly elevated in breast cancer tissues. Therefore, we explored whether LINC00667 level is increased in TXT-resistant TNBC cell-derived exosomes. In addition, whether exosomal LINC00667 derived from TXT-resistant TNBC cell could affect TXT sensitivity in TXT-sensitive TNBC cells was investigated as well. In the present study, exosomes were isolated from the TXT-resistant TNBC cells and from TXT-sensitive TNBC cells. Next, the level of LINC00667 in the isolated exosomes was detected with RT-qPCR. We found that LINC00667 expression was obviously elevated in TXT-resistant TNBC cell-derived exosomes compared to that in TXT-sensitive TNBC cell-derived exosomes. In addition, LINC00667 could be transferred from TXT-resistant TNBC cells to TNBC cells via exosomes. Moreover, TXT-resistant TNBC cell secreted exosomal LINC00667 markedly reduced the sensitivity of TNBC cells to TXT via upregulation of Bcl-2. Meanwhile, downregulation of LINC00667 notably enhanced the sensitivity of TXT-resistant TNBC cells to TXT through downregulation of Bcl-2. Additionally, LINC00667 was considered to be a ceRNA to sponge miR-200b-3p, thereby elevating Bcl-2 expression. Collectively, TXT-resistant TNBC cell-derived exosomal LINC00667 could decrease the chemosensitivity of TNBC cells to TXT via regulating miR-200b-3p/Bcl-2 axis. These findings suggested that LINC00667 might serve as a promising target for enhancing sensitivity of TNBC cells to TXT therapy.

Genomic Alterations Affecting Competitive Endogenous RNAs (ceRNAs) and Regulatory Networks (ceRNETs) with Clinical Implications in Triple-Negative Breast Cancer (TNBC)

“…They reviewed many miRNAs, circRNAs and lncRNAs that have implications on chemoresistance in TNBC and hypothesized that ncRNA profiling will be a viable means of selecting a chemotherapy that is likely to garner a response. Examples in the works of literature of ceRNAs that affect the response to chemotherapies include circ_0001667, conferring Adriamycin resistance; LINC00667, conferring docetaxel resistance; BORG, conferring doxorubicin resistance; UBAP, HCP5 and DLX6-AS1, conferring cisplatin resistance; and FTH1P3 and H19, conferring paclitaxel resistance ( Table 2 ) [ 50 , 51 , 66 , 67 , 68 , 69 , 70 , 71 ]. Given the complicated mechanisms of chemoresistance with many effector proteins playing a role, targeting key ceRNA regulatory networks to cover multiple mechanisms or as more reliable markers that are based on a greater number of functional factors may be promising.…”

Long Noncoding RNAs in Taxane Resistance of Breast Cancer

“…Similarly, the study found that the expression level of LINC00667 was significantly higher in docetaxel-resistant TNBC cell-derived exosomes than in docetaxel-sensitive TNBC cell-derived exosomes. Exosomal LINC00667 was found to promote the resistance of TNBC cells to docetaxel by regulating the miR-200b-3p/Bcl-2 axis [159]. Additionally, in breast cancer, LINC00461 can act as a ceRNA by directly interacting with miR-411-5p and promotes docetaxel resistance by acting as a sponge for miR-411-5p molecules [171].…”