MicroRNA-1254 Suppresses Epithelial-Mesenchymal Transition by Upregulating c-Cellular Myelocytomatosis Oncogene (c-Myc) and Alleviates Drug Resistance in Lung Cancer

Drug resistance is a huge challenge during the management of diseases. MicroRNA (miRNA) dys-regulation is known to contribute to tumor progression. Herein we aimed to explore miR-1254’s role in drug resistance in lung cancer. In the present study, we used Pabolizumab to treat drug-resistant and non-drug resistant lung cancer cells followed by analysis of miR-1254 expression by RT-qPCR, epithelial-mesenchymal transition (EMT) related protein and c-Myc expression by western blot, E-cadherin and N-cadherin level by immunofluorescence. Additionally, mouse model of lung cancer was treated with miR-1254 mimic and/or Pabolizumab to assess miR-1254’s role in lung cancer in vivo. Drug-resistant lung cancer cells exhibited significantly increased viability upon treatment with Pabolizumab with decreased miR-1254 expression. Besides, Pabolizumab upregulated E-caderin and downregulated N-cadherin. Importantly, miR-1254 bound to c-Myc in cancer cells. In the presence of miR-1254 mimic or siRNA (si)-c-Myc, the chemosensitivity of lung cancer cells was increased whereas miR-1254 inhibitor augmented cell resistance to Pabolizumab. Furthermore, the chemosensitivity induced by c-Myc could be depleted by miR-1254 inhibitor. Combined treatment of miR-1254 mimic and Pabolizumab significantly decreased tumor weight and volume, and reduced c-Myc level. In conclusion, miR-1254 might suppress EMT by inhibiting c-Myc expression in lung cancer and decrease drug resistance.

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LncRNA SNHG4 promotes the proliferation, migration, invasiveness, and epithelial–mesenchymal transition of lung cancer cells by regulating miR-98-5p

Biochemistry and Cell Biology ◽

10.1139/bcb-2019-0065 ◽

2019 ◽

Vol 97 (6) ◽

pp. 767-776 ◽

Cited By ~ 7

Author(s):

Yufu Tang ◽

Lijian Wu ◽

Mingjing Zhao ◽

Guangdan Zhao ◽

Shitao Mao ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Cells ◽

Cell Lines ◽

Noncoding Rna ◽

Epithelial Mesenchymal Transition ◽

Lung Cancer Cells ◽

Mesenchymal Transition ◽

Gene 4

Long noncoding RNA small nucleolar RNA host gene 4 (SNHG4) is usually up-regulated in cancer and regulates the malignant behavior of cancer cells. However, its role in lung cancer remains elusive. In this study, we silenced the expression of SNHG4 in NCI-H1437 and SK-MES-1, two representative non-small-cell lung cancer cell lines, by transfecting them with siRNA (small interfering RNA) that specifically targets SNHG4. We observed significantly inhibited cell proliferation in vitro and reduced tumor growth in vivo after SNHG4 silencing. SNHG4 knockdown also led to cell cycle arrest at the G1 phase, accompanied with down-regulation of cyclin-dependent kinases CDK4 and CDK6. The migration and invasiveness of these two cell lines were remarkably inhibited after SNHG4 silencing. Moreover, our study revealed that the epithelial–mesenchymal transition (EMT) of lung cancer cells was suppressed by SNHG4 silencing, as evidenced by up-regulated E-cadherin and down-regulated SALL4, Twist, and vimentin. In addition, we found that SNHG4 silencing induced up-regulation of miR-98-5p. MiR-98-5p inhibition abrogated the effect of SNHG4 silencing on proliferation and invasion of lung cancer cells. In conclusion, our findings demonstrate that SNHG4 is required by lung cancer cells to maintain malignant phenotype. SNHG4 probably exerts its pro-survival and pro-metastatic effects by sponging anti-tumor miR-98-5p.

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Extracellular and macropinocytosis internalized ATP work together to induce epithelial–mesenchymal transition and other early metastatic activities in lung cancer

Cancer Cell International ◽

10.1186/s12935-019-0973-0 ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 10

Author(s):

Yanyang Cao ◽

Xuan Wang ◽

Yunsheng Li ◽

Maria Evers ◽

Haiyun Zhang ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Purinergic Receptor ◽

Lung Cancer Cells ◽

Migration And Invasion ◽

Western Blots ◽

Mesenchymal Transition

Abstract Background Extracellular ATP (eATP) was shown to induce epithelial–mesenchymal transition (EMT), a very important early process in metastasis, in cancer cells via purinergic receptor signaling. However, the exact induction mechanisms are far from fully known. We previously described that eATP is internalized by cancer cells in vitro and in vivo by macropinocytosis in human non-small cell lung cancer A549 and other cancer cells, drastically elevates intracellular ATP levels, enhances cell proliferation and resistance to anticancer drugs. In this study, we tested the hypothesis that eATP and macropinocytosis-internalized eATP also induces EMT and other early steps of metastasis. Methods Floating cells, fencing, and transwell assays were used to show that ATP induces cell detachment, new colony formation, migration and invasion in human A549 and other lung cancer cells. Western blots were used to detect ATP-induced changes in EMT-related proteins; Confocal microscopy was used to demonstrate ATP-induced metastasis-related cell morphological changes. Inhibitors and siRNA knockdowns were used to determine P2X7’s involvement in the ATP-induced EMT. CRISPR–Cas9 knockout of the SNX5 gene was used to identify macropinocytosis’ roles in EMT and cancer cell growth both in vitro and in vivo. Student t-test and one-way ANOVA were used to determine statistical significance, P < 0.05 was considered significant. Results eATP potently induces expression of matrix metallopeptidases (MMPs), and detachment, EMT, migration, and invasion of lung cancer cells. The induction was independent of TGF-β and semi-independent of P2X7 activation. eATP performs these functions not only extracellularly, but also intracellularly after being macropinocytically internalized to further enhance P2X7-mediated EMT, filopodia formation and other early steps of metastasis. The knockout of macropinocytosis-associated SNX5 gene significantly reduces macropinocytosis, slows down tumor growth, and changes tumor morphology in nude mice. Conclusions Collectively, these results show that eATP's functions in these processes not only from outside of cancer cells but also inside after being macropinocytotically internalized. These findings shed light on eATP’s initiator and effector roles in almost every step in early metastasis, which calls for rethinking and rebalancing energy equations of intracellular biochemical reactions and the Warburg effect, and identifies eATP and macropinocytosis as novel targets for potentially slowing down EMT and preventing metastasis.

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Toxicarioside O Inhibits Cell Proliferation and Epithelial-Mesenchymal Transition by Downregulation of Trop2 in Lung Cancer Cells

Frontiers in Oncology ◽

10.3389/fonc.2020.609275 ◽

2021 ◽

Vol 10 ◽

Author(s):

Wu-Ping Zheng ◽

Feng-Ying Huang ◽

Shu-Zhen Dai ◽

Jin-Yan Wang ◽

Ying-Ying Lin ◽

...

Keyword(s):

Lung Cancer ◽

Cell Proliferation ◽

Cancer Cells ◽

Molecular Mechanisms ◽

Anticancer Agent ◽

Epithelial Mesenchymal Transition ◽

Lung Cancer Cells ◽

Mesenchymal Transition

Toxicarioside O (TCO), a natural product derived from Antiaris toxicaria, has been identified to be a promising anticancer agent. In this study, we aimed to investigate the effect of TCO on the proliferation and epithelial-mesenchymal transition (EMT) of lung cancer cells and its molecular mechanisms. Here, we indicated that TCO inhibits the proliferation of lung cancer cells both in vitro and in vivo. Our results demonstrated that TCO induces apoptosis in lung cancer cells. Moreover, we found that TCO suppresses EMT program and inhibits cell migration in vitro. Mechanistically, TCO decreases the expression of trophoblast cell surface antigen 2 (Trop2), resulting in inhibition of the PI3K/Akt pathway and EMT program. Overexpression of Trop2 rescues TCO-induced inhibition of cell proliferation and EMT. Our findings demonstrate that TCO markedly inhibits cell proliferation and EMT in lung cancer cells and provides guidance for its drug development.

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