LINC00626 promotes the malignant process of lung adenocarcinoma metastasis through the JAK1/STAT3/KHSRP axis_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

XU Feng ¹ ^# , FAN Linlin ² ^# , KANG Xia ² , LIU Yangyang ² ,  WEI Haitao ³ ,  LI Li ^2,3

1. Department of Respiratory Medicine, Huaihe Hospital, Henan University, Kaifeng, Henan 475001, P. R. China;
2. School of Nursing and Health, Henan University, Kaifeng, Henan 475001, P. R. China;
3. Department of Thoracic Surgery, Huaihe Hospital, Henan University, Kaifeng, Henan 475001, P. R. China;

Corresponding?author：

WEI Haitao, Email: taoge9885@163.com; LI Li, Email: 10210051@vip.henu.edu.cn

Keywords：

Lung adenocarcinoma; long intergenic non-protein coding RNA 626; JAK1; STAT3; KH-type splicing regulatory protein

DOI：

10.7507/1671-6205.202306023

Video：

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Objective To explore the molecular mechanism of LINC00626 regulating malignant progression of lung adenocarcinoma metastasis through JAK1/STAT3/KHSRP axis. Methods Quantitative real-time polymerase chain polymerase chain reaction was used to detect the expression of LINC00626 and KHSRP mRNA in human non-small-cell lung carcinoma cell lines (A549, H1299, H1975, H1437), human normal bronchial epithelial cell line (16HBE) and 144 lung adenocarcinoma tissues. The knockdown LINC00626 lentivirus and the control lentivirus were transferred into H1299 and H1437 cells, and named as sh-LINC00626 group (silencing of LINC00626 by transfecting short hairpin RNA lentiviral vector and sh-NC Group negative control by transfecting short hairpin RNA lentiviral). The overexpressed LINC00626 lentivirus and the control lentivirus were transferred into A549 and H1975 cells and named as LINC00626 group and Vector group. KHSRP vector on the basis of silencing LINC00626 and blank vector on the basis of silencing LINC00626 were added in H1437 cells. Cell counting kit-8 assay and Transwell migration/invasion assay were used to detect cell proliferation, migration and invasion. The expression levels of JAK/STAT and KHSRP in stably transfected cells were detected by Western blot. The effect of LINC00626 in vivo was studied in nude mice. Nuclear-cytoplasmic separation and RNA fluorescence in situ hybridization assay are used to predict the subcellular localization of LINC00626 and KHSRP. RNA pull down and mass spectrometry analysis were used to identify LINC00626 binding proteins. Results The expression levels of LINC00626 and KHSRP in non-small-cell lung carcinoma cell lines were significantly higher than those in normal human bronchial epithelial cells. LINC00626 and KHSRP were highly expressed in lung adenocarcinoma. Compared with the control group, the cell proliferation rate, colony formation, cell migration and invasion of H1437 cells were significantly decreased in knockdown group, while the reverse was true for over-expression. LINC00626 and KHSRP were located in the nucleus. LINC00626 directly binded to the KHSRP protein. Compared with the control group, H1437 cells transfected with knockdown LINC00626 and KHSRP significantly increased cell proliferation rate, cell migration, number of invasions. Compared with the control group, knockdown group showed a significant decrease in tumor volume and weight, cell proliferation rate and proliferation index, and the number of lung metastases. While the overexpression group showed an opposite effect, there were significant differences among the groups (P<0.01). The expression of JAK1 and STAT3 mRNA and protein in sh-LINC00626 group was lower than that in sh-NC Group (P<0.05), and the expression of JAK1 and STAT3 mRNA and protein in sh-LINC00626 group was higher than that in Vector group (P<0.05). Conclusion LINC00626 promotes malignant progression of lung adenocarcinoma metastasis through JAK1/STAT3/KHSRP signaling axis.

Citation： XU Feng, FAN Linlin, KANG Xia, LIU Yangyang, WEI Haitao, LI Li. LINC00626 promotes the malignant process of lung adenocarcinoma metastasis through the JAK1/STAT3/KHSRP axis. Chinese Journal of Respiratory and Critical Care Medicine, 2023, 22(9): 646-656. doi: 10.7507/1671-6205.202306023 Copy

1.	Feng HM, Zhao Y, Yan WJ, et al. Genomic and immunogenomic analysis of three prognostic signature genes in LUAD. BMC bioinformatics, 2023, 24(1): 19.
2.	Li X, Dai Z, Wu X, et al. The Comprehensive Analysis Identified an Autophagy Signature for the Prognosis and the Immunotherapy Efficiency Prediction in Lung Adenocarcinoma. Front Immunol, 2022, 13: 749241.
3.	Liu Y, Yu M, Cheng X, et al. A novel LUAD prognosis prediction model based on immune checkpoint-related lncRNAs. Front Genet, 2022, 13: 1016449.
4.	李靜, 劉曉琴, 楊業, et al. LncRNA KCNQ1OT1在非小細胞肺癌組織中的表達及其臨床意義. 中國呼吸與危重監護雜志, 2016, 15(5): 453-457.
5.	Lou Y, Shi Q, Zhang Y, et al. Multi-Omics Signatures Identification for LUAD Prognosis Prediction Model Based on the Integrative Analysis of Immune and Hypoxia Signals. Front Cell Dev Biol, 2022, 10: 840466.
6.	Barton M, Santucci-Pereira J, Vaccaro OG, et al. BC200 overexpression contributes to luminal and triple negative breast cancer pathogenesis. BMC Cancer, 2019, 19(1): 994.
7.	Sun J, Guo Y, Bie B, et al. Silencing of long noncoding RNA HOXD-AS1 inhibits proliferation, cell cycle progression, migration and invasion of hepatocellular carcinoma cells through MEK/ERK pathway. J Cell Biochem, 2020, 121(1): 443-457.
8.	Chen Z, Hu Z, Sui Q, et al. LncRNA FAM83A-AS1 facilitates tumor proliferation and the migration via the HIF-1α/ glycolysis axis in lung adenocarcinoma. Int J Biol Sci, 2022, 18(2): 522-535.
9.	Lin Z, Feng F, Liang J, et al. lncRNA RP11-10A14.5: a potential prognosis biomarker for LUAD through regulation on proliferation and metastasis. Discov Oncol, 2022, 13(1): 32.
10.	Liu Y, Liang L, Ji L, et al. Potentiated lung adenocarcinoma (LUAD) cell growth, migration and invasion by lncRNA DARS-AS1 via miR-188-5p/ KLF12 axis. Aging (Albany NY), 2021, 13(19): 23376-23392.
11.	Xing C, Sun SG, Yue ZQ, et al. Role of lncRNA LUCAT1 in cancer. Biomed Pharmacother, 2021, 134: 111158.
12.	Hin Tang JJ, Hao Thng DK, Lim JJ, et al. JAK/STAT signaling in hepatocellular carcinoma. Hepat Oncol, 2020, 7(1): Hep18.
13.	Liu C, Feng H, Song L, et al. Synergistic effects of thalidomide and cisplatin are mediated via the PI3K/AKT and JAK1/STAT3 signaling pathways in cervical cancer. Oncol Rep, 2022, 48(4): 169.
14.	Taniuchi K, Ogasawara M. KHSRP-bound small nucleolar RNAs associate with promotion of cell invasiveness and metastasis of pancreatic cancer. Oncotarget, 2020, 11(2): 131-147.
15.	Pan R, Cai W, Sun J, et al. Inhibition of KHSRP sensitizes colorectal cancer to 5-fluoruracil through miR-501-5p-mediated ERRFI1 mRNA degradation. J Cell Physiol, 2020, 235(2): 1576-1587.
16.	Xu F, Huang X, Li Y, et al. m(6)A-related lncRNAs are potential biomarkers for predicting prognoses and immune responses in patients with LUAD. Mol Ther Nucleic Acids, 2021, 24: 780-791.
17.	Wu S, Huang X, Tie X, et al. Role and mechanism of action of circular RNA and laryngeal cancer. Pathol Res Pract, 2021, 223: 153460.
18.	羅汶鑫, 李為民. 肺癌的表觀遺傳學研究進展及其臨床意義. 中國呼吸與危重監護雜志, 2018, 17(3): 313-318.
19.	Zhang G, Sun J, Zhang X. A novel Cuproptosis-related LncRNA signature to predict prognosis in hepatocellular carcinoma. Sci Rep, 2022, 12(1): 11325.
20.	Song J, Sun Y, Cao H, et al. A novel pyroptosis-related lncRNA signature for prognostic prediction in patients with lung adenocarcinoma. Bioengineered, 2021, 12(1): 5932-5949.
21.	Song H, Liu Y, Jin X, et al. Long non-coding RNA LINC01535 promotes cervical cancer progression via targeting the miR-214/EZH2 feedback loop. J Cell Mol Med, 2019, 23(9): 6098-6111.
22.	He L, Tian L. Downregulation of miR–409–3p suppresses LPS–induced inflammation in human bronchial epithelial cells through SOCS3/JAK1/STAT3 signaling: The implication for bronchopneumonia. Mol Med Rep, 2021, 23(3): 190.
23.	Zhao X, Cheng Z, Wang J. Long Noncoding RNA FEZF1-AS1 Promotes Proliferation and Inhibits Apoptosis in Ovarian Cancer by Activation of JAK-STAT3 Pathway. Med Sci Monit, 2018, 24: 8088-8095.
24.	Jiang Y, Xu CH, Zhao Y, et al. LINC00926 is involved in hypoxia-induced vascular endothelial cell dysfunction via miR-3194-5p regulating JAK1/STAT3 signaling pathway. Eur J Histochem, 2023, 67(1): 3526.
25.	Chen YD, Cai FY, Mao YZ, et al. The anti-neoplastic activities of aloperine in HeLa cervical cancer cells are associated with inhibition of the IL-6-JAK1-STAT3 feedback loop. Chin J Nat Med, 2021, 19(11): 815-824.
26.	Du Y, Zhang JY, Gong LP, et al. Hypoxia-induced ebv-circLMP2A promotes angiogenesis in EBV-associated gastric carcinoma through the KHSRP/VHL/HIF1α/VEGFA pathway. Cancer Lett, 2022, 526: 259-272.
27.	Ide S, Toiyama Y, Shimura T, et al. Angiopoietin-Like Protein 2 Acts as a Novel Biomarker for Diagnosis and Prognosis in Patients with Esophageal Cancer. Ann Surg Oncol, 2015, 22(8): 2585-2592.
28.	Briata P, Bordo D, Puppo M, et al. Diverse roles of the nucleic acid-binding protein KHSRP in cell differentiation and disease. Wiley Interdiscip Rev RNA, 2016, 7(2): 227-240.
29.	Yuan H, Deng R, Zhao X, et al. SUMO1 modification of KHSRP regulates tumorigenesis by preventing the TL-G-Rich miRNA biogenesis. Mol Cancer, 2017, 16(1): 157.
30.	Yan M, Sun L, Li J, et al. RNA-binding protein KHSRP promotes tumor growth and metastasis in non-small cell lung cancer. J Exp Clin Cancer Res, 2019, 38(1): 478.

1. Feng HM, Zhao Y, Yan WJ, et al. Genomic and immunogenomic analysis of three prognostic signature genes in LUAD. BMC bioinformatics, 2023, 24(1): 19.
2. Li X, Dai Z, Wu X, et al. The Comprehensive Analysis Identified an Autophagy Signature for the Prognosis and the Immunotherapy Efficiency Prediction in Lung Adenocarcinoma. Front Immunol, 2022, 13: 749241.
3. Liu Y, Yu M, Cheng X, et al. A novel LUAD prognosis prediction model based on immune checkpoint-related lncRNAs. Front Genet, 2022, 13: 1016449.
4. 李靜, 劉曉琴, 楊業, et al. LncRNA KCNQ1OT1在非小細胞肺癌組織中的表達及其臨床意義. 中國呼吸與危重監護雜志, 2016, 15(5): 453-457.
5. Lou Y, Shi Q, Zhang Y, et al. Multi-Omics Signatures Identification for LUAD Prognosis Prediction Model Based on the Integrative Analysis of Immune and Hypoxia Signals. Front Cell Dev Biol, 2022, 10: 840466.
6. Barton M, Santucci-Pereira J, Vaccaro OG, et al. BC200 overexpression contributes to luminal and triple negative breast cancer pathogenesis. BMC Cancer, 2019, 19(1): 994.
7. Sun J, Guo Y, Bie B, et al. Silencing of long noncoding RNA HOXD-AS1 inhibits proliferation, cell cycle progression, migration and invasion of hepatocellular carcinoma cells through MEK/ERK pathway. J Cell Biochem, 2020, 121(1): 443-457.
8. Chen Z, Hu Z, Sui Q, et al. LncRNA FAM83A-AS1 facilitates tumor proliferation and the migration via the HIF-1α/ glycolysis axis in lung adenocarcinoma. Int J Biol Sci, 2022, 18(2): 522-535.
9. Lin Z, Feng F, Liang J, et al. lncRNA RP11-10A14.5: a potential prognosis biomarker for LUAD through regulation on proliferation and metastasis. Discov Oncol, 2022, 13(1): 32.
10. Liu Y, Liang L, Ji L, et al. Potentiated lung adenocarcinoma (LUAD) cell growth, migration and invasion by lncRNA DARS-AS1 via miR-188-5p/ KLF12 axis. Aging (Albany NY), 2021, 13(19): 23376-23392.
11. Xing C, Sun SG, Yue ZQ, et al. Role of lncRNA LUCAT1 in cancer. Biomed Pharmacother, 2021, 134: 111158.
12. Hin Tang JJ, Hao Thng DK, Lim JJ, et al. JAK/STAT signaling in hepatocellular carcinoma. Hepat Oncol, 2020, 7(1): Hep18.
13. Liu C, Feng H, Song L, et al. Synergistic effects of thalidomide and cisplatin are mediated via the PI3K/AKT and JAK1/STAT3 signaling pathways in cervical cancer. Oncol Rep, 2022, 48(4): 169.
14. Taniuchi K, Ogasawara M. KHSRP-bound small nucleolar RNAs associate with promotion of cell invasiveness and metastasis of pancreatic cancer. Oncotarget, 2020, 11(2): 131-147.
15. Pan R, Cai W, Sun J, et al. Inhibition of KHSRP sensitizes colorectal cancer to 5-fluoruracil through miR-501-5p-mediated ERRFI1 mRNA degradation. J Cell Physiol, 2020, 235(2): 1576-1587.
16. Xu F, Huang X, Li Y, et al. m(6)A-related lncRNAs are potential biomarkers for predicting prognoses and immune responses in patients with LUAD. Mol Ther Nucleic Acids, 2021, 24: 780-791.
17. Wu S, Huang X, Tie X, et al. Role and mechanism of action of circular RNA and laryngeal cancer. Pathol Res Pract, 2021, 223: 153460.
18. 羅汶鑫, 李為民. 肺癌的表觀遺傳學研究進展及其臨床意義. 中國呼吸與危重監護雜志, 2018, 17(3): 313-318.
19. Zhang G, Sun J, Zhang X. A novel Cuproptosis-related LncRNA signature to predict prognosis in hepatocellular carcinoma. Sci Rep, 2022, 12(1): 11325.
20. Song J, Sun Y, Cao H, et al. A novel pyroptosis-related lncRNA signature for prognostic prediction in patients with lung adenocarcinoma. Bioengineered, 2021, 12(1): 5932-5949.
21. Song H, Liu Y, Jin X, et al. Long non-coding RNA LINC01535 promotes cervical cancer progression via targeting the miR-214/EZH2 feedback loop. J Cell Mol Med, 2019, 23(9): 6098-6111.
22. He L, Tian L. Downregulation of miR–409–3p suppresses LPS–induced inflammation in human bronchial epithelial cells through SOCS3/JAK1/STAT3 signaling: The implication for bronchopneumonia. Mol Med Rep, 2021, 23(3): 190.
23. Zhao X, Cheng Z, Wang J. Long Noncoding RNA FEZF1-AS1 Promotes Proliferation and Inhibits Apoptosis in Ovarian Cancer by Activation of JAK-STAT3 Pathway. Med Sci Monit, 2018, 24: 8088-8095.
24. Jiang Y, Xu CH, Zhao Y, et al. LINC00926 is involved in hypoxia-induced vascular endothelial cell dysfunction via miR-3194-5p regulating JAK1/STAT3 signaling pathway. Eur J Histochem, 2023, 67(1): 3526.
25. Chen YD, Cai FY, Mao YZ, et al. The anti-neoplastic activities of aloperine in HeLa cervical cancer cells are associated with inhibition of the IL-6-JAK1-STAT3 feedback loop. Chin J Nat Med, 2021, 19(11): 815-824.
26. Du Y, Zhang JY, Gong LP, et al. Hypoxia-induced ebv-circLMP2A promotes angiogenesis in EBV-associated gastric carcinoma through the KHSRP/VHL/HIF1α/VEGFA pathway. Cancer Lett, 2022, 526: 259-272.
27. Ide S, Toiyama Y, Shimura T, et al. Angiopoietin-Like Protein 2 Acts as a Novel Biomarker for Diagnosis and Prognosis in Patients with Esophageal Cancer. Ann Surg Oncol, 2015, 22(8): 2585-2592.
28. Briata P, Bordo D, Puppo M, et al. Diverse roles of the nucleic acid-binding protein KHSRP in cell differentiation and disease. Wiley Interdiscip Rev RNA, 2016, 7(2): 227-240.
29. Yuan H, Deng R, Zhao X, et al. SUMO1 modification of KHSRP regulates tumorigenesis by preventing the TL-G-Rich miRNA biogenesis. Mol Cancer, 2017, 16(1): 157.
30. Yan M, Sun L, Li J, et al. RNA-binding protein KHSRP promotes tumor growth and metastasis in non-small cell lung cancer. J Exp Clin Cancer Res, 2019, 38(1): 478.

Chinese Journal of Respiratory and Critical Care Medicine

LINC00626 promotes the malignant process of lung adenocarcinoma metastasis through the JAK1/STAT3/KHSRP axis

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