As a Novel Tumor Suppressor, LHPP Promotes Apoptosis by Inhibiting the PI3K/AKT Signaling Pathway in Oral Squamous Cell Carcinoma

Abstract

Oral squamous cell carcinoma (OSCC) refers to the malignant tumor of the head and neck with a highest morbidity. It exhibits a poor prognosis and unsatisfactory treatment partially attributed to delayed diagnosis. As indicated from existing reports, the protein histidine phosphatase LHPP acts as a vital factor in tumorigenesis in liver, lung, bladder, breast and pancreatic tumor tissues. Thus far, the functional mechanism of LHPP in OSCC remains unclear. DGE analysis, OSCC cell lines and OSCC cases were found that LHPP was down-regulated in OSCC tissues and cells compared with that in normal oral mucosa tissues and cells, and was closely related to OSCC differentiation. Cell counting Kit 8 test, EdU proliferation test, scratches test, invasion test, monoclonal formation test, mouse xenograft tumor model, HE staining and immunohistochemistry showed that LHPP inhibited OSCC growth, proliferation and migration in vivo and in vitro. GO and KEGG enrichment analysis, LHPP transcription factor analysis and flow cytometry found that LHPP promotes the apoptosis of OSCC by decreasing the transcriptional activity of p-PI3K and p-Akt. Finally, our results suggested that LHPP inhibited the progression of OSCC through the PI3K/AKT signaling pathway, indicating that LHPP may be a new target for the treatment of OSCC.

LHPP suppresses gastric cancer progression via the PI3K/AKT/mTOR signaling pathway

“…Research has shown that the AKT/mTOR, NF-κB, and ERK/MAPK signaling pathways are closely related to tumor EMT 13 , 14 . Besides, LHPP has been proven to have a strong connection with PI3K/AKT 7 , 9 , 15 , 16 . Thus, we examined whether LHPP affects biological behavior through PI3K/AKT/mTOR axis in GC.…”

“…Subsequent researches with cell- or animal-based evidence support the correlation between LHPP and tumorgenesis had been widely conducted. LHPP was found to be down-regulated and associated with cancer progression and favorable prognosis in many cancers 7 - 9 . Our research group also reported functional links between LHPP and tumorigenesis in colorectal cancer 10 , 11 .…”

Risk SNP‐mediated LINC01614 upregulation drives head and neck squamous cell carcinoma progression via PI3K/AKT signaling pathway

“…GO functional annotation analysis showed that these genes were mainly enriched in extracellular matrix and cell adhering binding (Figure5Band Supporting Information: FigureS2). The PI3K/AKT signaling pathway is one of the most frequently activated pathways in the occurrence and development of HNSCC, which can promote cancer progression by promoting the proliferation, growth, and metabolism of cancer cells [45][46][47]. Therefore, we evaluated whether LINC01614 could regulate PI3K/AKT signaling pathway.…”

Quantitation of phosphohistidine in proteins in a mammalian cell line by 31P NMR

“…The importance of pHis to higher eukaryotes is further illustrated by the growing number of histidine kinases, phosphotransferases [ 46 ] and phosphatases that have been characterised. This includes the NME family of likely histidine kinases [ 47 , 48 ], as well as the protein histidine phosphatase LHPP which has multifaceted activity as a tumour suppressor for a range of cancers [ 12 , 14 ], and the histidine phosphatase PHPT1, which is an oncogene involved in lung cancer [ 49 ]. To date there is good evidence for these proteins’ involvement in cancers, but little biochemical evidence that their function is due to histidine phosphorylation/dephosphorylation.…”

“…It was first observed in eukaryotes in 1962 [ 11 ], and has attracted attention recently stimulated by the finding that the enzyme histidine phosphatase, LHPP, has a role as a tumor suppressor [ 12 ]. Since this observation, LHPP has been found to play a role in a wide range of cancers [ 13 ], with the suggestion that its function is to inhibit the PI3 kinase / protein kinase B (AKT) signaling pathway [ 14 ]. Several eukaryotic enzymes have now been identified that phosphorylate histidine, or dephosphorylate pHis [ 15 ], and there is a database of histidine phosphorylation sites [ 16 ].…”