LHPP Inhibits the Viability, Migration, and Proliferation of PDAC Cells and Significantly Affects the Expression of SDC1 and S100p

Abstract

Introduction Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a poor response to chemotherapy and an extremely poor prognosis. Recent studies have revealed that phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) can inhibit the growth of various cancers. Therefore, the current study was conducted to investigate the antitumor effects of LHPP in PDAC and to explore its mechanism using proteomics analysis. Methods and Results Immunohistochemical analysis of clinical samples demonstrated that LHPP expression levels were lower in tumor tissues compared to adjacent nontumor tissues. Moreover, multivariate COX regression analysis showed that LHPP expression level was an independent prognostic factor for the patients with PDAC. Patients with high LHPP expression had a better prognosis. The lentiviral vectors for normal control (NC), LHPP knockdown (KD), and LHPP overexpression (OE) were infected with BxPC-3 and PANC-1 cell lines. Cell counting kit-8 assay, Transwell assay, and flow cytometry analyses showed that LHPP overexpression significantly inhibited the cell viability, migration, and proliferation of BxPC-3 and PANC-1 cells. Moreover, xenograft tumor model demonstrated that LHPP overexpression inhibited xenograft tumor growth in vivo. Subsequently, proteins with significantly altered expression in BxPC-3 cells after lentivirus infection were detected using proteomics analyses. Interestingly, compared to the NC group, the expression of Syndecan 1 (SDC1) was significantly upregulated in the KD group, while that of S100P was significantly downregulated in the OE group. Conclusion LHPP might emerge as an important target for delaying the advancement of PDAC, thereby providing a novel therapeutic approach for the treatment of PDAC.

LHPP expression in triple-negative breast cancer promotes tumor growth and metastasis by modulating the tumor microenvironment

“…However, LHPP protein levels in these cancer types have not been confirmed in cancer cell lines, mouse models, or patient samples, and further work would be required to determine whether LHPP might have a tumor-promoting role in these cancers. In addition, LHPP levels were higher in the tumor cells compared to normal tissues in a mouse PDAC model (44), suggesting a tumor-promoting role for LHPP in this cancer type, in contrast to prior reports for PDAC (20, 45).…”

Oncolytic adenovirus encoding LHPP exerts potent antitumor effect in lung cancer

“…In recent years, phosphoinositide phosphohistidine inorganic pyrophosphate phosphatase (LHPP), a histidine phosphatase, has been shown to be a new tumor suppressor [12] .Low expression of LHPP has also been found in cancer tissues of bladder cancer [13] , lung cancer, pancreatic cancer [14,15] , cervical cancer [16] , papillary thyroid cancer [17] , and colorectal cancer [18,19] .Overexpression of LHPP protein inhibits hepatocellular carcinoma cell growth and metastasis, and also reduces the transcription of CCM1, PKM2, MMP7, and MMP9 in cancer cells, and that high expression of LHPP was negatively correlated with cell cycle and metastasis, among others [20] . It suggests that LHPP is lung cancer suppressor with potent.…”