RNA-binding protein (RBP) has a highly dynamic spatiotemporal regulation process and important biological functions. They are critical to maintain the transcriptome through post-transcriptionally ...controlling the processing and transportation of RNA, including regulating RNA splicing, polyadenylation, mRNA stability, mRNA localization, and translation. Alteration of each process will affect the RNA life cycle, produce abnormal protein phenotypes, and thus lead to the occurrence and development of tumors. Here, we summarize RBPs involved in tumor progression and the underlying molecular mechanisms whereby they are regulated and exert their effects. This analysis is an important step towards the comprehensive characterization of post-transcriptional gene regulation involved in tumor progression.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Gastric cancer stem cells (CSCs) are the main causes of metastasis and drug resistance. We previously indicated that miR-375 can inhibit Helicobacter pylori-induced gastric carcinogenesis; here, we ...aim to explore the effects and mechanisms of miR-375 on gastric cancer (GC) cell stemness.
Lentivirus infection was used to construct GC cells with ectopic expression of miR-375. In vitro and in vivo experiments, including analysis of tumor spheroid formation, CD44+ sub-population with stemness, stemness marker expression, and tumor-initiating ability, were performed to evaluate the effects of miR-375 on the stemness of GC cells. Furthermore, microarray and bioinformatics analysis were performed to search the potential targets of miR-375 in GC cells. Luciferase reporter, RNA immunoprecipitation, and RNA-FISH assays were carried out to verify the targeting of miR-375. Subsequently, combined with tissue microarray analysis, erastin-resistant GC cells, transmission electron microscopy, a series of agonists and oxidative stress markers, the underlying mechanisms contributing to miR-375-mediated effects were explored.
MiR-375 reduced the stemness of GC cells in vitro and in vivo. Mechanistically, SLC7A11 was identified as a direct target of miR-375 and miR-375 attenuated the stemness of GC cells mainly through triggering SLC7A11-dependent ferroptosis.
MiR-375 can trigger the ferroptosis through targeting SLC7A11, which is essential for miR-375-mediated inhibition on GC cell stemness. These results suggest that the miR-375/SLC7A11 regulatory axis could serve as a potential target to provoke the ferroptosis and thus attenuate the stemness of GC cells.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Targeting cancer stem cells is critical for suppressing cancer progression and recurrence. Finding novel markers or related pathways could help eradicate or diagnose cancer in clinic.
By constructing ...STARD13-correlated ceRNA 3'UTR stable overexpression or knockdown breast cancer cells, we aimed to explore the effects of STARD13-correlated ceRNA network on breast cancer stemness in vitro and in vivo. Further RNA-sequencing was used to analyze transcriptome change in combination with functional studies on candidate signaling. Clinical samples obtained from The Cancer Genome Atlas data were used to validate the correlation between STARD13 and related pathways. Finally, in vitro and in vivo experiments were used to examine the effects of STARD13-correlated ceRNA network on chemotherapy sensitivity/resistance.
Here, we revealed that this ceRNA network inhibited stemness of breast cancer. Mechanistically, we found that activation of STARD13-correlated ceRNA network was negatively correlated with YAP/TAZ activity in breast cancer. Specifically, this ceRNA network attenuated YAP/TAZ nuclear accumulation and transcriptional activity via collectively modulating Hippo and Rho-GTPase/F-actin signaling. Finally, we demonstrated that YAP/TAZ transcriptional activity regulated by this ceRNA network was involved in chemoresistance.
Our results uncover a novel mechanism of YAP/TAZ activation in breast cancer and propose the possibility to drive STARD13-correlated ceRNA network to inhibit breast cancer stem cell traits.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
MiRNA is a type of small non-coding RNA, by regulating downstream gene expression that affects the progression of multiple diseases, especially cancer. MiRNA can participate in the biological ...processes of tumor, including proliferation, invasion and escape, and exhibit tumor enhancement or inhibition. The tumor immune microenvironment contains numerous immune cells. These cells include lymphocytes with tumor suppressor effects such as CD8+ T cells and natural killer cells, as well as some tumor-promoting cells with immunosuppressive functions, such as regulatory T cells and myeloid-derived suppressor cells. MiRNA can affect the tumor immune microenvironment by regulating the function of immune cells, which in turn modulates the progression of tumor cells. Investigating the role of miRNA in regulating the tumor immune microenvironment will help elucidate the specific mechanisms of interaction between immune cells and tumor cells, and may facilitate the use of miRNA as a predictor of immune disorders in tumor progression. This review summarizes the multifarious roles of miRNA in tumor progression through regulation of the tumor immune microenvironment, and provides guidance for the development of miRNA drugs to treat tumors and for the use of miRNA as an auxiliary means in tumor immunotherapy.
The expression of CYP4Z1 and the pseudogene CYP4Z2P has been shown to be specifically increased in breast cancer by our group and others. Additionally, we previously revealed the roles of the ...competitive endogenous RNA (ceRNA) network mediated by these genes (ceRNET_CC) in breast cancer angiogenesis, apoptosis, and tamoxifen resistance. However, the roles of ceRNET_CC in regulating the stemness of breast cancer cells and the mechanisms through which ceRNET_CC is regulated remain unclear.
Transcriptional factor six2, CYP4Z1-3'UTR, and CYP4Z2P-3'UTR were stably overexpressed or knocked down in breast cancer cells via lentivirus infection. ChIP-sequencing and RNA-sequencing analysis were performed to reveal the mechanism through which ceRNET_CC is regulated and the transcriptome change mediated by ceRNET_CC. Clinical samples were used to validate the correlation between six2 and ceRNET_CC. Finally, the effects of the six2/ceRNET_CC axis on the stemness of breast cancer cells and chemotherapy sensitivity were evaluated by in vitro and in vivo experiments.
We revealed that ceRNET_CC promoted the stemness of breast cancer cells. Mechanistically, six2 activated ceRNET_CC by directly binding to their promoters, thus activating the downstream PI3K/Akt and ERK1/2 pathways. Finally, we demonstrated that the six2/ceRNET_CC axis was involved in chemoresistance.
Our results uncover the mechanism through which ceRNET_CC is regulated, identify novel roles for the six2/ceRNET_CC axis in regulating the stemness of breast cancer cells, and propose the possibility of targeting the six2/ceRNET_CC axis to inhibit breast cancer stem cell (CSC) traits.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Chemotherapy is a major anticancer therapeutic modality, however, multidrug resistance (MDR) is frequently observed and hinders treatment efficacy. Here, we investigated the role and potential ...mechanism of the long noncoding RNA (lncRNA) FENDRR in adriamycin resistance of chronic myeloid leukaemia (CML) cells. FENDRR overexpression attenuates adriamycin resistance, as shown by increased Rhodamine 123 accumulation, promotion of cell apoptosis in vitro and suppression of tumour growth in vivo. Mechanistically, we identified that FENDRR reduces the interaction of the RNA‐binding protein HuR with MDR1 via acting as a sponge, and miR‐184 competitively binds to FENDRR with HuR. Thus, the HuR/FENDRR/miR‐184 interaction contributes to MDR1 activity. These findings indicate that FENDRR is a potential target for reversing adriamycin resistance.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The relapse of breast cancer could be due to the existence of breast cancer stem cells (BCSCs). Other and our researches have indicated the suppressive roles of miR-375 in various tumors, however, ...its roles in breast cancer stemness remain confusing. Here, we constructed breast cancer cells with miR-375 stable overexpression via lentivirus infection. Flow cytometry, Western blot, mammosphere formation, cell colony formation and CCK8 as well as in vivo assays were performed to identify the role of miR-375 in the stemness of breast cancer cells. Luciferase reporter, RNA-Fluorescence in situ hybridization (RNA-FISH) and RNA-binding protein immunoprecipitation (RIP) assays were utilized to elucidate the mechanism whereby miR-375 exerts its effects. It was found that miR-375 not only reduced the stemness, but also decreased adriamycin resistance of breast cancer cells. These results were characterized by the decrease of BCSC rate, mammosphere-forming and tumor-initiating ability, and IC50 value of adriamycin, and weakened by JAK2 re-expression. This work indicates that miR-375 suppresses the stemness of breast cancer cells through targeting JAK2.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Tanshinone IIA is the active constituent extracted from Salvia Miltiorrhza. Numerous studies have shown that Tanshinone IIA could inhibit tumor proliferation and metastasis, including gastric cancer. ...However, the effect of Tanshinone IIA on gastric cancer cell stemness stays unclear. Here, we found that Tanshinone IIA could reduce gastric cancer cell stemness through detecting spheroid‐forming, flow cytometry analysis, and the expression of stemness markers (OCT3/4, ALDH1A1, and CD44). Mechanistically, Tanshinone IIA increased the level of lipid peroxides and decreased glutathione level in gastric cancer cells, both of which are the markers of ferroptosis. Similarly, ferroptosis inducers (erastin, sulfasalazine, and sorafenib) reduced gastric cancer cell stemness. Additionally, the inhibitory effects of Tanshinone IIA on GC cell stemness were reversed by ferroptosis inhibitor (Fer‐1) or overexpression of SLC7A11, which is a critical ferroptosis inhibitor. Therefore, we revealed that Tanshinone IIA inhibited the stemness of gastric cancer cells partly through inducing ferroptosis.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Breast cancer stem cells have self-renewal capability and are resistant to conventional chemotherapy. PD-L1 could promote the expression of stemness markers (OCT4 and Nanog) in breast cancer stem ...cells. However, the mechanisms by which PD-L1 regulates the stemness of breast cancer cells and PD-L1 is regulated in breast cancer cells are still unclear.
Lentivirus infection was used to construct stable cell lines. The correlation between PD-L1 and stemness markers expression was evaluated in clinical samples. Additionally, luciferase reporter assay combined with RNA-Fluorescence in situ hybridization (RNA-FISH) and RNA-binding protein immunoprecipitation (RIP) assays were used to verify the direct binding of miR-873 on PD-L1. Furthermore, flow cytometry, mammosphere formation combined with nude mouse tumor xenograft model were carried out to examine the effects of miR-873/PD-L1 axis on the stemness of breast cancer cells. Finally, MTT assay was performed to determine the effects of miR-873/PD-L1 axis on drug resistance.
PD-L1 expression was positively correlated with the expression of stemness markers, and overexpression of PD-L1 contributed to chemoresistance and stemness-like properties in breast cancer cells via activating PI3K/Akt and ERK1/2 pathways. Mechanistically, miR-873 inhibited PD-L1 expression through directly binding to its 3′-untranslated region (UTR), and miR-873 attenuated the stemness and chemoresistance of breast cancer cells which was dependent on PD-L1 and the downstream PI3K/Akt and ERK1/2 signaling. Notably, the promotion of PD-L1 on the stemness and chemoresistance was enhanced by recombinant PD-1 (rPD-1), this effect was attenuated by PD-1/PD-L1 inhibitor.
miR-873/PD-L1 regulatory axis might serve as a therapeutic target to enhance the chemo-sensitivity and eliminate the stemness of breast cancer cells.
This work was supported by the National Nature Science Foundation of China, No. 81702957, China Postdoctoral Science Foundation, No. 2017M620230, the Postdoctoral Research Funding Scheme of Jiangsu Province (2017), No. 1701197B, and the Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions.
•A critical role of PD-L1 in stemness and chemoresistance is proposed.•A negative miR-873/PD-L1 interaction was identified in breast cancer cells.•The mechanisms of miR-873/PD-L1 in stemness and chemoresistance were studied.•The results provide new insights for breast cancer progression and treatment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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