LPAL2 Suppresses Tumor Growth and Metastasis of Hepatocellular Carcinoma by Modulating MMP9 Expression

Yang-Hsiang Lin; Yu-Chin Liu; Cheng-Yi Chen; Hsiang-Cheng Chi; Meng-Han Wu; Po-Shuan Huang; Cheng-Chih Chang; Tzu-Kang Lin; Chau-Ting Yeh; Kwang-Huei Lin

doi:10.3390/cells11162610

LPAL2 Suppresses Tumor Growth and Metastasis of Hepatocellular Carcinoma by Modulating MMP9 Expression

Cells. 2022 Aug 22;11(16):2610. doi: 10.3390/cells11162610.

Authors

Yang-Hsiang Lin¹, Yu-Chin Liu^{2

3

4}, Cheng-Yi Chen⁵, Hsiang-Cheng Chi^{6

7}, Meng-Han Wu³, Po-Shuan Huang³, Cheng-Chih Chang⁸, Tzu-Kang Lin^{9

10}, Chau-Ting Yeh¹, Kwang-Huei Lin^{1

3

4

11}

Affiliations

¹ Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan 333, Taiwan.
² Molecular Medicine Research Center, Chang Gung University, Taoyuan 244, Taiwan.
³ Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan.
⁴ Department of Biochemistry, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan.
⁵ Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.
⁶ Graduate Institute of Integrated Medicine, China Medical University, Taichung 40447, Taiwan.
⁷ Chinese Medicine Research Center, China Medical University, Taichung 406040, Taiwan.
⁸ Department of General Surgery, Chang Gung Memorial Hospital at Chia-yi, Chia-yi 613, Taiwan.
⁹ Neurosurgery, School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City 24205, Taiwan.
¹⁰ Neurosurgery, Department of Surgery, Fu Jen Catholic University Hospital, New Taipei City 24352, Taiwan.
¹¹ Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 33303, Taiwan.

Abstract

Tumor metastasis is a complex process modulated by both intrinsic and extrinsic factors that ultimately result in poorer patient outcomes, including diminished survival. Pseudogene-derived long non-coding RNAs (lncRNA) play important roles in cancer progression. In the current study, we found that the pseudogene-derived lncRNA LPAL2 is downregulated in hepatocellular carcinoma (HCC) tissues, and further showed that elevated LPAL2 expression is positively correlated with survival outcome. The knockdown of LPAL2 in hepatoma cells induced tumor formation, migration, invasion, sphere formation, and drug resistance. Metalloproteinase 9 (MMP9) was identified as an LPAL2-regulated target gene, consistent with clinical findings that LPAL2 expression is significantly associated with MMP9 expression. Furthermore, patients with a higher expression of LPAL2 and lower expression of MMP9 (LPAL2-high/MMP9-low) had a higher survival rate than those with other combinations. Collectively, our findings establish LPAL2 as a novel tumor suppressor in HCC, and suggest targeting LPAL2 and MMP9 as a therapeutic approach for the treatment of HCC.

Keywords: LPAL2; MMP9; cancer stem cell; hepatocellular carcinoma; metastasis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apolipoprotein A-II / metabolism*
Carcinoma, Hepatocellular* / pathology
Humans
Liver Neoplasms* / pathology
Matrix Metalloproteinase 9 / genetics
Matrix Metalloproteinase 9 / metabolism
Neoplastic Processes
RNA, Long Noncoding* / genetics

Substances

APOA2 protein, human
Apolipoprotein A-II
RNA, Long Noncoding
MMP9 protein, human
Matrix Metalloproteinase 9

Grants and funding

This work was supported by grants from Chang Gung Memorial Hospital, Taoyuan, Taiwan (CMRPD1L0111 to KHL; CMRPG3L1211 and NRRPG3L6011 to YHL) and from the Ministry of Science and Technology of the Republic of China (MOST 106-2320-B-182-032-MY3; 109-2320-B-182-011; 110-2320-B-182-032 to KHL; MOST 110-2311-B-182A-001-MY3 to YHL).