The novel miR-873-5p-YWHAE-PI3K/AKT axis is involved in non-small cell lung cancer progression and chemoresistance by mediating autophagy.

Non-small cell lung cancer (NSCLC) encompasses approximately 85% of all lung cancer cases and is the foremost cancer type worldwide; it is prevalent in both sexes and known for its high fatality rate. Expanding scientific inquiry underscores the indispensability of microRNAs in NSCLC. Here, we probed the impact of miR-873-5p on NSCLC development and chemoresistance. qRT‒PCR was used to measure the miR-873-5p level in NSCLC cells with or without chemoresistance. A model of miR-873-5p overexpression was constructed. The proliferation and viability of NSCLC cells were evaluated through CCK8 and colony formation experiments. Cell migration and invasion were monitored via Transwell assays. Western blotting was used to determine the levels of YWHAE, PI3K, AKT, EMT, apoptosis, and autophagy-related proteins. The sensitivity of NSCLC cells to the chemotherapeutic agent gefitinib was assessed. Additionally, the correlation of YWHAE with miR-873-5p was validated via a dual-luciferase reporter assay and RNA immunoprecipitation (RIP). Overexpressed miR-873-5p suppressed migration, proliferation, invasion, and EMT while concurrently stimulating apoptotic processes. miR-873-5p was downregulated in NSCLC cells resistant to gefitinib. Upregulating miR-873-5p reversed gefitinib resistance by inducing autophagy. YWHAE was confirmed to be a downstream target of miR-873-5p. YWHAE overexpression promoted the malignant behaviors of NSCLC cells and boosted tumor growth, while these effects were reversed following miR-873-5p overexpression. Subsequent investigations revealed that overexpressing YWHAE promoted PI3K/AKT pathway activation, with miR-873-5p displaying inhibitory effects on the YWHAE-mediated PI3K/AKT signaling cascade. miR-873-5p affects proliferation, invasion, migration, EMT, autophagy, and chemoresistance in NSCLC by controlling the YWHAE/PI3K/AKT axis.

Circ_MBNL3 Restrains Hepatocellular Carcinoma Progression by Sponging miR-873-5p to Release PHF2.

Background Circular RNAs (circRNAs) have shown key regulatory roles in human malignancies. The working mechanism of circRNAs in hepatocellular carcinoma (HCC) remains to be elucidated. Methods Cell proliferation was analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, 5-ethynyl-20-deoxyuridine (EdU) assay, and colony formation assay. Xenograft tumor model was established to analyze the role of circ_MBNL3 on tumor growth in vivo. Results Circ_MBNL3 expression was notably down-regulated in HCC tissues and cell lines. Circ_MBNL3 overexpression suppressed the proliferation, migration, and invasion and induced the apoptosis of HCC cells. miR-873-5p directly targeted the 3' untranslated region (3'UTR) of PHF2, and PHF2 was negatively regulated by miR-873-5p in HCC cells. miR-873-5p silencing-induced anti-tumor influences were largely reversed by the interference of PHF2 in HCC cells. Circ_MBNL3 restrained xenograft tumor growth in vivo. Conclusion Circ_MBNL3 restrained the proliferation, migration, and invasion and promoted the apoptosis of HCC cells depending on the regulation of miR-873-5p/PHF2 axis.

Circ_0005615 Regulates the Progression of Colorectal Cancer Through the miR-873-5p/FOSL2 Signaling Pathway.

To determine the effects of circ_0005615 in CRC development and underneath mechanism. The expression levels of circ_0005615, microRNA-873-5p (miR-873-5p) and FOS-like antigen 2 (FOSL2) mRNA were determined by quantitative real-time polymerase chain reaction (qRT-PCR). The protein levels of exosome makers, proliferation-related makers and FOSL2 were detected by western blot or immunohistochemistry assay. Cell proliferation was evaluated by cell counting kit-8 (CCK-8) and cell colony formation assays. Cell migration and invasion were demonstrated by a transwell assay. Cell apoptosis was investigated by flow cytometry analysis. The binding relationship between miR-873-5p and circ_0005615 or FOSL2 was predicted by circular RNA interactome and targetscan online databases, respectively, and identified by dual-luciferase reporter assay. The impacts of circ_0005615 silencing on tumor formation were determined by in vivo tumor formation assay. Circ_0005615 expression was dramatically upregulated in serum exosomes of CRC patients compared with the control group. The CRC patients with a high circ_0005615 expression had a poor survival rate. Circ_0005615 and FOSL2 expressions were apparently increased, while miR-873-5p was decreased in CRC tissues or cells relative to control groups. Circ_0005615 knockdown inhibited cell proliferation, migration, and invasion, whereas promoted cell apoptosis in CRC; however, miR-873-5p inhibitor attenuated these impacts. Additionally, circ_0005615 acted as a sponge of miR-873-5p and miR-873-5p bound to FOSL2. FOSL2 overexpression restrained the effects of miR-873-5p mimic on CRC progression. Furthermore, circ_0005615 knockdown suppressed tumor growth in vivo. Circ_0005615 modulated CRC malignant progression by controlling FOSL2 expression through sponging miR-873-5p. This finding lays a foundation for the study on circRNA-mediated CRC therapy.

Circular RNA hsa_circ_0000277 promotes tumor progression and DDP resistance in esophageal squamous cell carcinoma.

BACKGROUND: Circular RNAs (circRNAs) are well-known regulators of cancer progression and chemoresistance in various types of cancers. This study was performed to investigate the function of hsa_circ_0000277 in esophageal squamous cell carcinoma (ESCC). METHODS: RNA levels were analyzed via the reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Cell Counting Kit-8 (CCK-8) assay was applied to determine cell proliferation and half maximal inhibitory concentration (IC50) of cisplatin (DDP). Colony formation ability was evaluated by colony formation assay. Cell cycle and apoptosis were measured using flow cytometry. RNA immunoprecipitation (RIP), pull-down assay and dual-luciferase reporter assays were performed for target interaction analysis. The protein levels were determined through western blot. Xenograft models were established for researching hsa_circ_0000277 function in vivo. RESULTS: Hsa_circ_0000277 expression was increased in ESCC cells and tissues, and it had important clinical significance. Downregulation of hsa_circ_0000277 repressed ESCC cell proliferation, colony formation, cell cycle, and DDP resistance. Hsa_circ_0000277 acted as a microRNA-873-5p (miR-873-5p) sponge and Sry-related high-mobility group box 4 (SOX4) was validated as a target of miR-873-5p. Moreover, hsa_circ_0000277/miR-873-5p axis and miR-873-5p/SOX4 axis regulated ESCC cell progression and DDP resistance. Hsa_circ_0000277/miR-873-5p axis activated SOX4/Wnt/ß-catenin signaling pathway. Hsa_circ_0000277 facilitated tumorigenesis and DDP resistance by miR-873-5p/SOX4 axis in vivo. CONCLUSION: These findings unraveled that hsa_circ_0000277 promoted ESCC progression and DDP resistance via miR-873-5p/SOX4/Wnt/ß-catenin axis, showing a specific molecular mechanism of carcinogenesis and chemoresistance in ESCC.

MiR-873-5p modulates progression of tongue squamous cell carcinoma via targeting SEC11A.

OBJECTIVE: To explore the effect of miR-873-5p on proliferation, apoptosis, migration, and invasion of tongue squamous cell carcinoma (TSCC) by targeting SEC11A. METHODS: Tongue squamous cell carcinoma tissues were collected and performed by qRT-PCR and Western blotting to determine the expression of miR-873-5p and SPC18. SCC9 and CAL-27 cells were transfected and divided into Mock, mimic NC, miR-873-5p mimic, SEC11A, and miR-873-5p mimic + SEC11A groups. Then, a series of experiments including cell count kit 8 (CCK-8), wound healing, Transwell, and flow cytometry were conducted. Besides, Western blotting was used to detect the expression of SPC18 and EGFR pathway-related proteins. RESULTS: MiR-873-5p was downregulated while SPC18 was upregulated in TSCC, and miR-873-5p was negatively correlated with SPC18. Dual luciferase reporter gene assay confirmed SEC11A to be a target of miR-873-5p. Cell proliferation, migration, and invasion of SCC9 and CAL-27 cells in miR-873-5p mimic group were decreased with increased cell apoptosis, presenting with downregulations of SPC18 and EGFR pathway-related proteins, while cells in SEC11A group manifested totally different changes. Moreover, the inhibitory effect of miR-873-5p mimic on TSCC cell growth was abolished by SEC11A overexpression. CONCLUSION: Overexpression of miR-873-5p may suppress cell proliferation, migration, and invasion, but facilitate apoptosis in TSCC via targeting SEC11A.

Hsa_circ_0058129 regulates papillary thyroid cancer development via miR-873-5p/follistatin-like 1 axis.

BACKGROUND: Papillary thyroid cancer (PTC) is an endocrine malignancy with a high incidence. Circular RNAs (circRNAs) participate in regulating PTC. Here, we analyzed the role of hsa_circ_0058129 (circ_0058129) in PTC. METHODS: The expression of circ_0058129, fibronectin 1 (FN1) mRNA, microRNA-873-5p (miR-873-5p), and follistatin-like 1 (FSTL1) was detected by qRT-PCR and western blot. Cell proliferation was analyzed by CCK-8, EdU, and flow cytometry analysis assays. Cell migration and invasion were evaluated by Transwell assay. The targeting relationship of miR-873-5p and circ_0058129 or FSTL1 was identified through dual-luciferase reporter assay, RIP assay, and RNA pull-down assay. Xenograft mouse model assay was implemented to determine the effect of circ_0058129 on tumor formation in vivo. RESULTS: The circ_0058129 and FSTL1 abundances were increased, while the miR-873-5p content was decreased in PTC tissues and cells compared with control groups. Circ_0058129 shortage inhibited PTC cell proliferation, migration, and invasion. Moreover, miR-873-5p repressed PTC cell malignancy by binding to FSTL1. Circ_0058129 targeted miR-873-5p to regulate FSTL1. CONCLUSION: Circ_0058129 expedited PTC progression through the miR-873-5p/FSTL1 pathway.

Hsa_circ_0045932 regulates the progression of colorectal cancer by regulating HK2 through sponging miR-873-5p.

BACKGROUND: Circular RNAs (circRNAs) have been confirmed to be key regulators for colorectal cancer (CRC) progression. The purpose of this research was to explore the biological role and mechanism of hsa_circ_0045932 in CRC. METHODS: RT-qPCR and Western blot (WB) were applied to examine RNA and protein levels, respectively. MTT assay, EdU assay, and transwell assay were used to detect cell proliferative, migration, and invasion. Glucose uptake and lactic acid level were determined to assess cellular glycolysis. Dual-luciferase reporter and RIP assays were carried out to detect the relationship between miR-873-5p and hsa_circ_0045932 or hexokinase 2 (HK2). Xenograft mice model was established to confirm the function of hsa_circ_0045932 in vivo. RESULTS: Hsa_circ_0045932 was overexpressed in CRC tissue samples and cells. Hsa_circ_0045932 knockdown repressed CRC cell proliferation, invasion, migration, and glycolysis abilities in vitro. MiR-873-5p could be sponged by hsa_circ_0045932, and its inhibitor also reversed the inhibitory effect of hsa_circ_0045932 knockdown on CRC cell progression. HK2 was targeted by miR-873-5p, and hsa_circ_0045932 regulated HK2 expression through targeting miR-873-5p. Overexpression of HK2 reversed the repressive effect of hsa_circ_0045932 knockdown on CRC cell malignant behaviors. Furthermore, the pro-tumor role of hsa_circ_0045932 in vivo was also confirmed using animal experiments. CONCLUSION: Hsa_circ_0045932 promoted CRC progression through sponging miR-873-5p to up-regulate HK2, which might offer novel therapeutic target for CRC clinical intervention.

Hsa_circ_0005529 promotes ZEB1 expression by regulating miR-873-5p and enhancing proliferation, invasion, and migration in gastric cancer cell lines.

BACKGROUND: Gastric cancer is a relatively common tumor. As circular RNAs (circRNAs) are documented to modulate proliferation and metastasis in various cancers, we evaluated the functions of circRNAs, in particular, hsa_circ_0005529, in gastric cancer cells. METHODS: Levels of hsa_circ_0005529 and miR-873-5p were examined by qRT-PCR, and the presence of hsa_circ_0005529 was confirmed by RNase R treatment. CCK-8, wound-healing, and Transwell assays were used to assess proliferation, migration, and invasion, respectively, while Western blotting was used to determine levels of zinc finger E-box-binding homeobox 1 (ZEB1) and dual-luciferase reporter assays to examine relationships between hsa_circ_0005529 and miR-873-5p. RESULTS: hsa_circ_0005529 was strongly expressed in gastric cancer where it stimulated tumorigenic behavior. Furthermore, hsa_circ_0005529 was shown to promote ZEB1 expression by sponging miR-873-5p, an inhibitor of ZEB1 expression. CONCLUSION: Our research showed that hsa_circ_0005529 promoted tumorigenic behavior in gastric cancer cells by adsorbing miR-873-5p to modulate ZEB1 levels. This suggests that hsa_circ_0005529 may be useful as a biomarker and target for diagnosing and treating gastric cancer.

Long non-coding RNA TDRG1 aggravates colorectal cancer stemness by binding with miR-873-5p to upregulate PRKAR2.

The effects of long non-coding RNA TDRG1 have been established in several tumors; however, its roles in colorectal cancer (CRC) progression are never been found. Here, we found that TDRG1 level was upregulated in CRC cells compared to that in normal colon epithelial cells. Additionally, TDRG1 level was remarkably upregulated in 3D non-adherent spheres derived from the parental CRC cells. Further in vitro and in vivo revealed that TDRG1 knockdown suppressed the stemness of CRC cells. What's more, combined with bioinformatics analysis, luciferase reporter and RNA pull down experiments showed that TDRG1 could bind to miR-873-5p, downregulated its level and thus increase the expression of PRKAR2. Finally, it was shown that TDRG1 functioned through the miR-873-5p/PRKAR2 axis. This study demonstrated a novel TDRG1/miR-873-5p/PRKAR2 signaling in CRC progression.

Long noncoding RNA TDRG1 aggravates doxorubicin-induced cardiomyopathy by binding with miR-873-5p to upregulate PRKAR2.

Doxorubicin-induced cardiomyopathy (DCM) is a life-threatening event. The long noncoding RNAs (lncRNAs) have been reported with close associations with DCM, which may provide novel insight into pathophysiological mechanisms of DCM. DCM rat model and cell models were established using doxorubicin. Echocardiography analyses were performed to assess cardiac function. We found that testis developmental-related gene 1 (TDRG1) expression was upregulated in DCM rats and in doxorubicin-treated human umbilical vein endothelial cells (HUVECs). TDRG1 knockdown enhanced cell viability, promoted tube formation, and inhibited apoptosis of doxorubicin-treated HUVECs. Additionally, knockdown of TDRG1 alleviated cardiac injury in DCM rats. Mechanistically, miR-873-5p was identified to bind with TDRG1. In addition, protein kinase cAMP-dependent type II regulatory subunit alpha (PRKAR2) was confirmed to bind with miR-873-5p as a target mRNA. MiR-873-5p negatively regulated PRKAR2 mRNA and protein levels. At last, rescue assays indicated that the overexpression of PRKAR2 restored the effect of TDRG1 knockdown on doxorubicin-treated HUVEC angiogenesis and apoptosis. To conclude, TDRG1 aggravates DCM progression by binding with miR-873-5p to upregulate PRKAR2. This work suggested the potential of TDRG1 as a target for DCM treatment.