LncRNA BRCAT54 inhibits the tumorigenesis of non-small cell lung cancer by binding to RPS9 to transcriptionally regulate JAK-STAT and calcium pathway genes

Abstract Objectives: Increasing evidence suggest that long non-coding RNAs (lncRNAs) play critical roles in cancers. However, the expression pattern and underlying mechanisms of lncRNAs in non-small cell lung cancer (NSCLC) remain incompletely understood. This study aimed to elucidate the functions and molecular mechanisms of a certain lncRNA in NSCLC. Methods: LncRNA microarray was performed to identify differential expressed lncRNAs between pre- and postoperation plasma in NSCLC patients. The expression level of candidate lncRNA in NSCLC tissues, plasma and cells was determined by quantitative real-time PCR (qRT-PCR) and in situ hybridization. The functional roles of lncRNA were assessed in vitro and in vivo. Furthermore, RNA pull-down, RNA immunoprecipitation, microarray, qRT-PCR and rescue assays were conducted to explore the mechanism action of lncRNA in NSCLC cells. Results: We identified a novel lncRNA (BRCAT54), which was significantly upregulated in preoperative plasma, NSCLC tissues and NSCLC cells, and its higher expression was associated with better prognosis in patients with NSCLC. Overexpression of BRCAT54 inhibited proliferation, migration and activated apoptosis in NSCLC cells. Conversely, knockdown of BRCAT54 reversed the suppressive effects of BRCAT54. Moreover, overexpression of BRCAT54 repressed NSCLC cell growth in vivo. Mechanistically, BRCAT54 directly bound to RPS9. Knockdown of RPS9 substantially reversed the promoting effects of si-BRCAT54 on cell proliferation and enhanced the inhibitive effect of si-BRCAT54 on BRCAT54 expression. In addition, silencing of RPS9 activated JAK-STAT pathway and suppressed calcium signaling pathway gene expressions. Conclusion: This study identified BRCAT54 as a tumor suppressor in NSCLC. Targeting the BRCAT54 and RPS9 feedback loop might be a novel therapeutic strategy for NSCLC.

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Guaiazulene Triggers ROS-Induced Apoptosis and Protective Autophagy in Non-small Cell Lung Cancer

Frontiers in Pharmacology ◽

10.3389/fphar.2021.621181 ◽

2021 ◽

Vol 12 ◽

Author(s):

Qin Ye ◽

Li Zhou ◽

Ping Jin ◽

Lei Li ◽

Shuwen Zheng ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Molecular Mechanisms ◽

Small Cell ◽

Autophagic Flux ◽

Small Cell Lung ◽

Induced Apoptosis

Non-small cell lung cancer (NSCLC) is one of the most frequent cancers worldwide, yet effective treatment remains a clinical challenge. Guaiazulene (GYZ), a cosmetic color additive, has previously been characterized as a potential antitumor agent due to observed anticancer effects. However, the efficacy of GYZ in the treatment of NSCLC and the involved molecular mechanisms remain largely unknown. Here, we indicated a role for GYZ in the suppression of NSCLC both in vitro and in vivo via triggering reactive oxygen species (ROS)-induced apoptosis. Concomitantly, GYZ induced complete autophagic flux in NSCLC cells via inhibiting the Akt/mTOR signaling pathway, which displayed cytoprotective effect against GYZ-induced growth suppression. Accompanied with autophagy inhibition obviously enhanced the effects of GYZ. Notably, GYZ acts synergistically with paclitaxel in the suppression of NSCLC in vitro. Together, our results for the first time reported that GYZ suppressed the proliferation of NSCLC and suggested a potential strategy for inhibiting NSCLC growth by combinational use of GYZ and autophagy inhibitors.

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Anexelekto (AXL) Increases Resistance to EGFR-TKI and Activation of AKT and ERK1/2 in Non-Small Cell Lung Cancer Cells

Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics ◽

10.3727/096504016x14648701447814 ◽

2016 ◽

Vol 24 (5) ◽

pp. 295-303 ◽

Cited By ~ 20

Author(s):

Yaqiong Tian ◽

Zengli Zhang ◽

Liyun Miao ◽

Zhimin Yang ◽

Jie Yang ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Tyrosine Kinases ◽

Molecular Mechanisms ◽

Small Cell ◽

Small Cell Lung ◽

Downstream Targets

Recently, epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have revolutionized non-small cell lung cancer (NSCLC) treatment. However, resistance remains a major obstacle. Anexelekto (AXL) is a member of receptor tyrosine kinases (RTKs) and shares the same downstream signaling pathways with EGFR, such as PI3K/AKT and MAPK/ERK. AXL overexpression in resistant tumors has been implicated in many previous studies in vitro and in vivo. In this study, we further examined whether expression of AXL and its downstream targets increased in gefitinib-resistant PC9 cells (PC9GR). In addition, we hypothesize that knocking down AXL in PC9GR and overexpressing AXL in PC9 using genetic tools can restore and decrease the sensitivity to gefitinib, respectively. We found that silencing AXL could sensitize the resistance to gefitinib, and the downstream pathways were significantly inhibited. Interestingly, we also discovered that increased AXL expression did promote the resistance, and its downstream targets were activated accordingly. Then 69 NSCLC patients who harbored EGFR mutation were recruited to analyze the expression of AXL and the association between AXL expression and clinical characteristics. We found that 5 of the 69 patients were AXL positive (about 7%), and AXL was related to tumor differentiation and tumor size. In this study, we concluded that the molecular mechanisms of AXL mediated resistance involved in the increased activity of the PI3K/AKT and MAPK/ERK1/2 pathways, and AXL overexpression could promote resistance, but it can be weakened when AXL expression is silenced.

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lncRNAs as Potential Targets in Small Cell Lung Cancer: MYC -dependent Regulation

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520620666200721130700 ◽

2020 ◽

Vol 20 (17) ◽

pp. 2074-2081

Author(s):

Onur Tokgun ◽

Pervin E. Tokgun ◽

Kubilay Inci ◽

Hakan Akca

Keyword(s):

Lung Cancer ◽

Stem Cell ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Therapeutic Strategy ◽

Small Cell ◽

Small Cell Lung ◽

Expression Levels ◽

Qrt Pcr ◽

Shrna Vector

Background: Small Cell Lung Cancer (SCLC) is a highly aggressive malignancy. MYC family oncogenes are amplified and overexpressed in 20% of SCLCs, showing that MYC oncogenes and MYC regulated genes are strong candidates as therapeutic targets for SCLC. c-MYC plays a fundamental role in cancer stem cell properties and malignant transformation. Several targets have been identified by the activation/repression of MYC. Deregulated expression levels of lncRNAs have also been observed in many cancers. Objective: The aim of the present study is to investigate the lncRNA profiles which depend on MYC expression levels in SCLC. Methods: Firstly, we constructed lentiviral vectors for MYC overexpression/inhibition. MYC expression is suppressed by lentiviral shRNA vector in MYC amplified H82 and N417 cells, and overexpressed by lentiviral inducible overexpression vector in MYC non-amplified H345 cells. LncRNA cDNA is transcribed from total RNA samples, and 91 lncRNAs are evaluated by qRT-PCR. Results: We observed that N417, H82 and H345 cells require MYC for their growth. Besides, MYC is not only found to regulate the expressions of genes related to invasion, stem cell properties, apoptosis and cell cycle (p21, Bcl2, cyclinD1, Sox2, Aldh1a1, and N-Cadherin), but also found to regulate lncRNAs. With this respect, expressions of AK23948, ANRIL, E2F4AS, GAS5, MEG3, H19, L1PA16, SFMBT2, ZEB2NAT, HOTAIR, Sox2OT, PVT1, and BC200 were observed to be in parallel with MYC expression, whereas expressions of Malat1, PTENP1, Neat1, UCA1, SNHG3, and SNHG6 were inversely correlated. Conclusion: Targeting MYC-regulated genes as a therapeutic strategy can be important for SCLC therapy. This study indicated the importance of identifying MYC-regulated lncRNAs and that these can be utilized to develop a therapeutic strategy for SCLC.

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Inhibition of yes-associated protein suppresses migration, invasion, and metastasis in non-small cell lung cancer in vitro and in vivo

Clinical and Experimental Medicine ◽

10.1007/s10238-021-00738-4 ◽

2021 ◽

Author(s):

Tomoya Takeda ◽

Masanobu Tsubaki ◽

Shuji Genno ◽

Takuya Matsuda ◽

Yuuta Yamamoto ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Small Cell ◽

Invasion And Metastasis ◽

Small Cell Lung

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Tumour-derived exosomal lncRNA-SOX2OT promotes bone metastasis of non-small cell lung cancer by targeting the miRNA-194-5p/RAC1 signalling axis in osteoclasts

Cell Death and Disease ◽

10.1038/s41419-021-03928-w ◽

2021 ◽

Vol 12 (7) ◽

Author(s):

Jianjiao Ni ◽

Xiaofei Zhang ◽

Juan Li ◽

Zhiqin Zheng ◽

Junhua Zhang ◽

...

Keyword(s):

Lung Cancer ◽

Bone Metastasis ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Osteoclast Differentiation ◽

Small Cell ◽

Signalling Pathway ◽

Small Cell Lung

AbstractBone is a frequent metastatic site of non-small cell lung cancer (NSCLC), and bone metastasis (BoM) presents significant challenges for patient survival and quality of life. Osteolytic BoM is characterised by aberrant differentiation and malfunction of osteoclasts through modulation of the TGF-β/pTHrP/RANKL signalling pathway, but its upstream regulatory mechanism is unclear. In this study, we found that lncRNA-SOX2OT was highly accumulated in exosomes derived from the peripheral blood of NSCLC patients with BoM and that patients with higher expression of exosomal lncRNA-SOX2OT had significantly shorter overall survival. Additionally, exosomal lncRNA-SOX2OT derived from NSCLC cells promoted cell invasion and migration in vitro, as well as BoM in vivo. Mechanistically, we discovered that NSCLC cell-derived exosomal lncRNA-SOX2OT modulated osteoclast differentiation and stimulated BoM by targeting the miRNA-194-5p/RAC1 signalling axis and TGF-β/pTHrP/RANKL signalling pathway in osteoclasts. In conclusion, exosomal lncRNA-SOX2OT plays a crucial role in promoting BoM and may serve as a promising prognostic biomarker and treatment target in metastatic NSCLC.

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Docetaxel-loaded exosomes for targeting non-small cell lung cancer: preparation and evaluation in vitro and in vivo

Drug Delivery ◽

10.1080/10717544.2021.1951894 ◽

2021 ◽

Vol 28 (1) ◽

pp. 1510-1523

Author(s):

Ying Wang ◽

Mimi Guo ◽

Dingmei Lin ◽

Dajun Liang ◽

Ling Zhao ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Small Cell ◽

Small Cell Lung ◽

Preparation And Evaluation

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Upregulation of IL-11, an IL-6 Family Cytokine, Promotes Tumor Progression and Correlates with Poor Prognosis in Non-Small Cell Lung Cancer

Cellular Physiology and Biochemistry ◽

10.1159/000488166 ◽

2018 ◽

Vol 45 (6) ◽

pp. 2213-2224 ◽

Cited By ~ 19

Author(s):

Meng Zhao ◽

Yahui Liu ◽

Ran Liu ◽

Jin Qi ◽

Yongwang Hou ◽

...

Keyword(s):

Lung Cancer ◽

Cell Proliferation ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Poor Prognosis ◽

Epithelial Mesenchymal Transition ◽

Small Cell ◽

Small Cell Lung ◽

Mesenchymal Transition

Background/Aims: Cytokines are key players in tumorigenesis and are potential targets in cancer treatment. Although IL-6 has attracted considerable attention, interleukin 11 (IL-11), another member of the IL-6 family, has long been overlooked, and little is known regarding its specific function in non-small cell lung cancer (NSCLC). In this study, we explored IL-11’s role in NSCLC and the detailed mechanism behind it. Methods: Cell proliferation in response to IL-11 was determined by colony formation, BrdU incorporation and MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay. Cell motility was measured by Transwell and wound healing assays. NSCLC xenograft models were used to confirm oncogenic function of IL-11 in vivo. Immunohistochemical staining and western blot assay were performed to detect epithelial–mesenchymal transition (EMT) markers and cell signaling pathway alterations. Eighteen NSCLC patients and 5 normal lung samples were collected together with data from an online database to determine the link between IL-11 expression and malignant progression. Results: We observed that IL-11 was upregulated in NSCLC samples compared with normal tissue samples and correlated with poor prognosis. Data from in vitro and in vivo models indicated that IL-11 promotes cell proliferation and tumorigenesis. Cell migration and invasion were also enhanced by IL-11. Epithelial–mesenchymal transition (EMT) was also observed after IL-11 incubation. Furthermore, IL-11 activated AKT and STAT3 in our experimental models. In addition, we observed that hypoxia induced IL-11 expression in NSCLC cells. Deferoxamine (DFX) or dimethyloxalylglycine (DMOG) induced hypoxia-inducible factor 1-alpha (HIF1α) upregulation, which enhanced IL-11 expression in NSCLC cells. Conclusions: Taken together, our results indicate that IL-11 is an oncogene in NSCLC, and elucidating the mechanism behind it may provide insights for NSCLC treatment.

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