Oncogenic circRNA C190 Promotes Non-Small Cell Lung Cancer via Modulation of the EGFR/ERK Pathway

Afeez Adekunle Ishola; Chian Shiu Chien; Yi Ping Yang; Yueh Chien; Aliaksandr A. Yarmishyn; Ping Hsing Tsai; Jerry Chieh Yu Chen; Po Kuei Hsu; Yung Hung Luo; Yuh Min Chen; Kung Hou Liang; Yuan Tzu Lan; Teh Ia Huo; Hsin I. Ma; Ming Teh Chen; Mong Lien Wang; Shih-Hwa Chiou

doi:10.1158/0008-5472.CAN-21-1473

Oncogenic circRNA C190 Promotes Non-Small Cell Lung Cancer via Modulation of the EGFR/ERK Pathway

Afeez Adekunle Ishola, Chian Shiu Chien, Yi Ping Yang, Yueh Chien, Aliaksandr A. Yarmishyn, Ping Hsing Tsai, Jerry Chieh Yu Chen, Po Kuei Hsu, Yung Hung Luo, Yuh Min Chen, Kung Hou Liang, Yuan Tzu Lan, Teh Ia Huo, Hsin I. Ma, Ming Teh Chen, Mong Lien Wang^*, Shih-Hwa Chiou

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

72 Scopus citations

Abstract

Lung cancers are the leading cause of cancer-related mortality worldwide, and the majority of lung cancers are non-small cell lung carcinoma (NSCLC). Overexpressed or activated EGFR has been associated with a poor prognosis inNSCLC.Wepreviously identified a circular noncoding RNA, hsa_circ_0000190 (C190), as a negative prognostic biomarker of lung cancer. Here, we attempted to dissect the mechanistic function of C190 and test the potential of C190 as a therapeutic target in NSCLC. C190 was upregulated in both NSCLC clinical samples and cell lines. Activation of the EGFR pathway increased C190 expression through aMAPK/ERK-dependent mechanism. Transient and stable overexpression of C190 induced ERK1/2 phosphorylation, proliferation, and migration in vitro and xenograft tumor growth in vivo. RNA sequencing and Expression2Kinases (X2K) analysis indicated that kinases associated with cell-cycle and global translation are involved in C190-activated networks, including CDKs and p70S6K, which were further validated by immunoblotting. CRISPR/Cas13a-mediated knockdown of C190 decreased proliferation and migration of NSCLC cells in vitro and suppressed tumor growth in vivo. TargetScan and CircInteractome databases predicted that C190 targets CDKs by sponging miR-142-5p. Analysis of clinical lung cancer samples showed that C190, CDK1, and CDK6 expressions were significantly higher in advanced-stage lung cancer than in early-stage lung cancer. In summary, C190 is directly involved in EGFR- MAPK-ERK signaling and may serve as a potential therapeutic target for the treatment of NSCLC.

Original language	English
Pages (from-to)	75-89
Number of pages	15
Journal	Cancer Research
Volume	82
Issue number	1
DOIs	https://doi.org/10.1158/0008-5472.CAN-21-1473
State	Published - 1 Jan 2021

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10.1158/0008-5472.CAN-21-1473

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Ishola, A. A., Chien, C. S., Yang, Y. P., Chien, Y., Yarmishyn, A. A., Tsai, P. H., Chen, J. C. Y., Hsu, P. K., Luo, Y. H., Chen, Y. M., Liang, K. H., Lan, Y. T., Huo, T. I., Ma, H. I., Chen, M. T., Wang, M. L., & Chiou, S.-H. (2021). Oncogenic circRNA C190 Promotes Non-Small Cell Lung Cancer via Modulation of the EGFR/ERK Pathway. Cancer Research, 82(1), 75-89. https://doi.org/10.1158/0008-5472.CAN-21-1473

@article{ff69fec859fa4aa59d740d7fac0b48ba,

title = "Oncogenic circRNA C190 Promotes Non-Small Cell Lung Cancer via Modulation of the EGFR/ERK Pathway",

abstract = "Lung cancers are the leading cause of cancer-related mortality worldwide, and the majority of lung cancers are non-small cell lung carcinoma (NSCLC). Overexpressed or activated EGFR has been associated with a poor prognosis inNSCLC.Wepreviously identified a circular noncoding RNA, hsa_circ_0000190 (C190), as a negative prognostic biomarker of lung cancer. Here, we attempted to dissect the mechanistic function of C190 and test the potential of C190 as a therapeutic target in NSCLC. C190 was upregulated in both NSCLC clinical samples and cell lines. Activation of the EGFR pathway increased C190 expression through aMAPK/ERK-dependent mechanism. Transient and stable overexpression of C190 induced ERK1/2 phosphorylation, proliferation, and migration in vitro and xenograft tumor growth in vivo. RNA sequencing and Expression2Kinases (X2K) analysis indicated that kinases associated with cell-cycle and global translation are involved in C190-activated networks, including CDKs and p70S6K, which were further validated by immunoblotting. CRISPR/Cas13a-mediated knockdown of C190 decreased proliferation and migration of NSCLC cells in vitro and suppressed tumor growth in vivo. TargetScan and CircInteractome databases predicted that C190 targets CDKs by sponging miR-142-5p. Analysis of clinical lung cancer samples showed that C190, CDK1, and CDK6 expressions were significantly higher in advanced-stage lung cancer than in early-stage lung cancer. In summary, C190 is directly involved in EGFR- MAPK-ERK signaling and may serve as a potential therapeutic target for the treatment of NSCLC.",

author = "Ishola, {Afeez Adekunle} and Chien, {Chian Shiu} and Yang, {Yi Ping} and Yueh Chien and Yarmishyn, {Aliaksandr A.} and Tsai, {Ping Hsing} and Chen, {Jerry Chieh Yu} and Hsu, {Po Kuei} and Luo, {Yung Hung} and Chen, {Yuh Min} and Liang, {Kung Hou} and Lan, {Yuan Tzu} and Huo, {Teh Ia} and Ma, {Hsin I.} and Chen, {Ming Teh} and Wang, {Mong Lien} and Shih-Hwa Chiou",

note = "Publisher Copyright: {\textcopyright} 2021 American Association for Cancer Research.",

year = "2021",

month = jan,

day = "1",

doi = "10.1158/0008-5472.CAN-21-1473",

language = "English",

volume = "82",

pages = "75--89",

journal = "Cancer Research",

issn = "0008-5472",

publisher = "American Association for Cancer Research Inc.",

number = "1",

}

Ishola, AA, Chien, CS, Yang, YP, Chien, Y, Yarmishyn, AA, Tsai, PH, Chen, JCY, Hsu, PK, Luo, YH, Chen, YM, Liang, KH, Lan, YT, Huo, TI, Ma, HI, Chen, MT, Wang, ML & Chiou, S-H 2021, 'Oncogenic circRNA C190 Promotes Non-Small Cell Lung Cancer via Modulation of the EGFR/ERK Pathway', Cancer Research, vol. 82, no. 1, pp. 75-89. https://doi.org/10.1158/0008-5472.CAN-21-1473

TY - JOUR

T1 - Oncogenic circRNA C190 Promotes Non-Small Cell Lung Cancer via Modulation of the EGFR/ERK Pathway

AU - Ishola, Afeez Adekunle

AU - Chien, Chian Shiu

AU - Yang, Yi Ping

AU - Chien, Yueh

AU - Yarmishyn, Aliaksandr A.

AU - Tsai, Ping Hsing

AU - Chen, Jerry Chieh Yu

AU - Hsu, Po Kuei

AU - Luo, Yung Hung

AU - Chen, Yuh Min

AU - Liang, Kung Hou

AU - Lan, Yuan Tzu

AU - Huo, Teh Ia

AU - Ma, Hsin I.

AU - Chen, Ming Teh

AU - Wang, Mong Lien

AU - Chiou, Shih-Hwa

PY - 2021/1/1

Y1 - 2021/1/1

N2 - Lung cancers are the leading cause of cancer-related mortality worldwide, and the majority of lung cancers are non-small cell lung carcinoma (NSCLC). Overexpressed or activated EGFR has been associated with a poor prognosis inNSCLC.Wepreviously identified a circular noncoding RNA, hsa_circ_0000190 (C190), as a negative prognostic biomarker of lung cancer. Here, we attempted to dissect the mechanistic function of C190 and test the potential of C190 as a therapeutic target in NSCLC. C190 was upregulated in both NSCLC clinical samples and cell lines. Activation of the EGFR pathway increased C190 expression through aMAPK/ERK-dependent mechanism. Transient and stable overexpression of C190 induced ERK1/2 phosphorylation, proliferation, and migration in vitro and xenograft tumor growth in vivo. RNA sequencing and Expression2Kinases (X2K) analysis indicated that kinases associated with cell-cycle and global translation are involved in C190-activated networks, including CDKs and p70S6K, which were further validated by immunoblotting. CRISPR/Cas13a-mediated knockdown of C190 decreased proliferation and migration of NSCLC cells in vitro and suppressed tumor growth in vivo. TargetScan and CircInteractome databases predicted that C190 targets CDKs by sponging miR-142-5p. Analysis of clinical lung cancer samples showed that C190, CDK1, and CDK6 expressions were significantly higher in advanced-stage lung cancer than in early-stage lung cancer. In summary, C190 is directly involved in EGFR- MAPK-ERK signaling and may serve as a potential therapeutic target for the treatment of NSCLC.

AB - Lung cancers are the leading cause of cancer-related mortality worldwide, and the majority of lung cancers are non-small cell lung carcinoma (NSCLC). Overexpressed or activated EGFR has been associated with a poor prognosis inNSCLC.Wepreviously identified a circular noncoding RNA, hsa_circ_0000190 (C190), as a negative prognostic biomarker of lung cancer. Here, we attempted to dissect the mechanistic function of C190 and test the potential of C190 as a therapeutic target in NSCLC. C190 was upregulated in both NSCLC clinical samples and cell lines. Activation of the EGFR pathway increased C190 expression through aMAPK/ERK-dependent mechanism. Transient and stable overexpression of C190 induced ERK1/2 phosphorylation, proliferation, and migration in vitro and xenograft tumor growth in vivo. RNA sequencing and Expression2Kinases (X2K) analysis indicated that kinases associated with cell-cycle and global translation are involved in C190-activated networks, including CDKs and p70S6K, which were further validated by immunoblotting. CRISPR/Cas13a-mediated knockdown of C190 decreased proliferation and migration of NSCLC cells in vitro and suppressed tumor growth in vivo. TargetScan and CircInteractome databases predicted that C190 targets CDKs by sponging miR-142-5p. Analysis of clinical lung cancer samples showed that C190, CDK1, and CDK6 expressions were significantly higher in advanced-stage lung cancer than in early-stage lung cancer. In summary, C190 is directly involved in EGFR- MAPK-ERK signaling and may serve as a potential therapeutic target for the treatment of NSCLC.

UR - http://www.scopus.com/inward/record.url?scp=85122404619&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-21-1473

DO - 10.1158/0008-5472.CAN-21-1473

M3 - Article

C2 - 34753774

AN - SCOPUS:85122404619

SN - 0008-5472

VL - 82

SP - 75

EP - 89

JO - Cancer Research

JF - Cancer Research

IS - 1

ER -

Oncogenic circRNA C190 Promotes Non-Small Cell Lung Cancer via Modulation of the EGFR/ERK Pathway

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