Theranostics 2022; 12(13):5675-5690. doi:10.7150/thno.66230 This issue Cite

Research Paper

Lipid phosphate phosphatase-2 promotes tumor growth through increased c-Myc expression

Xiaoyun Tang1, Christopher R. Cromwell2, Rongzong Liu3, Roseline Godbout3, Basil P. Hubbard2, Todd P.W. McMullen4, David N. Brindley1✉

1. Department of Biochemistry and Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton, T6G 2S2, Canada
2. Department of Pharmacology, University of Alberta, Edmonton, T6G 2S2, Canada
3. Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, T6G 1Z2, Canada
4. Department of Surgery, University of Alberta, Edmonton, Alberta, T6G 2R7, Canada

Citation:
Tang X, Cromwell CR, Liu R, Godbout R, Hubbard BP, McMullen TPW, Brindley DN. Lipid phosphate phosphatase-2 promotes tumor growth through increased c-Myc expression. Theranostics 2022; 12(13):5675-5690. doi:10.7150/thno.66230. https://www.thno.org/v12p5675.htm
Other styles

File import instruction

Abstract

Graphic abstract

LPP2 is one of three enzymes in the lipid phosphate phosphatase family (LPP1-3) that dephosphorylate extracellular and intracellular bioactive lipid phosphates and pyrophosphates. LPP2 increases cell growth and LPP2 expression is elevated in a variety of malignancies, implying that LPP2 is a pro-tumorigenic factor.

Methods: LPP2 expression in human breast tumors and normal breast tissue was measured by qPCR. To understand the role of LPP2, we knocked out its expression in multiple cell lines using CRISPR/Cas9. Cell proliferation and migration were compared between wild type and LPP2 knockout cells. Cell cycle was measured by flow cytometry, and cell cycle proteins were determined by western blotting. Effects of LPP2 on tumor growth were investigated using syngeneic and xenograft mouse breast cancer models.

Results: LPP2 mRNA levels were higher in ER/PR positive, ER/HER2 positive, and triple negative human breast tumors, relative to normal breast tissue. Higher levels of LPP2 in breast tumors, hepatocellular carcinoma, pancreatic adenocarcinoma, and melanomas were prognostic of poorer survival. LPP2 mRNA expression is also increased in Hs-578T, MDA-MB-231, MCF7 and MDA-MB-468 breast cancer cell lines, relative to non-malignant Hs-578Bst, MCF10A and MCF-12A cells. LPP2 knockout in breast cancer cells decreased cell growth by inhibiting G1/S transition, whereas, increasing LPP2 levels in Hs-578Bst and MCF10A cells promoted proliferation. The effects of LPP2 on cell cycle were associated with changes in cyclin A2, cyclin B1, and cell cycle inhibitors, p27 or p21. The level of c-Myc was downregulated by knocking out LPP2, and it was partly restored by re-expressing LPP2. The positive correlation between the expression of LPP2 and c-Myc exists in multiple cancer cell lines including breast, lung, upper aerodigestive tract and urinary tract cancer. LPP2 knockout in MDA-MB-231 or 4T1 cells suppressed tumor formation in mouse breast cancer models, and decreased the in vivo expression of Ki67 and c-Myc of the cancer cells.

Conclusion: Targeting LPP2 could provide a new strategy for decreasing c-Myc expression and tumor growth.

Keywords: breast cancer, CRISPR/Cas9, cell cycle, cell proliferation, tumor growth


Citation styles

APA
Tang, X., Cromwell, C.R., Liu, R., Godbout, R., Hubbard, B.P., McMullen, T.P.W., Brindley, D.N. (2022). Lipid phosphate phosphatase-2 promotes tumor growth through increased c-Myc expression. Theranostics, 12(13), 5675-5690. https://doi.org/10.7150/thno.66230.

ACS
Tang, X.; Cromwell, C.R.; Liu, R.; Godbout, R.; Hubbard, B.P.; McMullen, T.P.W.; Brindley, D.N. Lipid phosphate phosphatase-2 promotes tumor growth through increased c-Myc expression. Theranostics 2022, 12 (13), 5675-5690. DOI: 10.7150/thno.66230.

NLM
Tang X, Cromwell CR, Liu R, Godbout R, Hubbard BP, McMullen TPW, Brindley DN. Lipid phosphate phosphatase-2 promotes tumor growth through increased c-Myc expression. Theranostics 2022; 12(13):5675-5690. doi:10.7150/thno.66230. https://www.thno.org/v12p5675.htm

CSE
Tang X, Cromwell CR, Liu R, Godbout R, Hubbard BP, McMullen TPW, Brindley DN. 2022. Lipid phosphate phosphatase-2 promotes tumor growth through increased c-Myc expression. Theranostics. 12(13):5675-5690.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Popup Image