Author(s)

ZhiGang Zhai¹, Yuan Fang², ZhenYu Xue³, Jian Guo⁴, Xiang Tang^2*

Affiliation(s)

¹Department of Thoracic Oncology, Affiliated Hospital of Jiangsu University, Zhenjiang 212013, Jiangsu, China.

²Department of Abdominal Oncology, Affiliated Hospital of Jiangsu University, Zhenjiang 212013, Jiangsu, China.

³Department of Head and Neck & Comprehensive Oncology, Affiliated Hospital of Jiangsu University, Zhenjiang 212013, Jiangsu, China.

⁴Department of Pathology, Affiliated Hospital of Jiangsu University, Zhenjiang 212013, Jiangsu, China.

Corresponding Author

Xiang Tang

ABSTRACT

Objective: To investigate the expression characteristics, clinical significance and underlying molecular mechanism of phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) in esophageal squamous cell carcinoma (ESCC), and to provide novel potential targets for the diagnosis, prognostic evaluation and clinical treatment of ESCC. Methods: The expression difference of LHPP mRNA between ESCC tissues and adjacent normal tissues was analyzed from the Gene Expression Omnibus (GEO) database including GSE20347, GSE38129 and GSE77861. A total of 15 pairs of ESCC tumor tissues and matched adjacent normal tissues, serum samples from 40 newly diagnosed ESCC patients and 20 healthy volunteers were collected. The expression level of LHPP was detected by quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA). Western blot was used to determine the protein expression of LHPP in ESCC cell lines (TE-1, KYSE-30, KYSE-150) and the normal esophageal epithelial cell line Het-1A. The correlation between LHPP expression and survival prognosis of ESCC patients was analyzed based on The Cancer Genome Atlas (TCGA) database. Differentially expressed genes (DEGs) between LHPP high and low expression groups were screened, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. The characteristics of tumor-infiltrating immune cells, the expression profiles of immune checkpoint genes and the sensitivity to five clinical common chemotherapeutic drugs including paclitaxel were further detected and compared between the two groups. Results: LHPP was significantly down-regulated in ESCC tissues, peripheral serum of ESCC patients and ESCC cell lines (P<0.05). ESCC patients with low LHPP expression had a markedly shortened median survival time (1.5 years vs 2.8 years), and the area under the curve (AUC) values of LHPP for predicting the 1-year, 2-year and 3-year overall survival rates of ESCC patients were 0.574, 0.615 and 0.671, respectively. DEGs in the LHPP low expression group were significantly enriched in biological processes including immune disorder, cell invasion and metastasis, and also enriched in classic tumor-promoting signaling pathways such as Wnt and TNF. In contrast, DEGs in the LHPP high expression group were enriched in physiological processes including cell junction, epidermal development and tissue homeostasis regulation, without enrichment of classic tumor-promoting or metastasis-promoting signaling pathways. The LHPP low expression group showed high infiltration of pro-tumor immune cells such as macrophages and B cells, and significantly up-regulated expression of core immune checkpoint genes including SIGLEC15 and CTLA4 (P<0.001). The LHPP high expression group had significantly higher sensitivity to paclitaxel, cisplatin, gemcitabine, 5-fluorouracil and irinotecan than the low expression group (P<0.05). Conclusion: LHPP is expressed deficiently in ESCC and acts as a tumor suppressor gene in the occurrence and development of ESCC. Low LHPP expression is closely associated with the poor prognosis of ESCC patients, and it may participate in the malignant progression of ESCC by regulating the activation of tumor-promoting signaling pathways, remodeling the tumor immunosuppressive microenvironment and reducing the sensitivity of tumor cells to chemotherapeutic drugs. LHPP can serve as a potential early diagnostic marker, prognostic evaluation indicator and therapeutic target for ESCC.

KEYWORDS

Esophageal squamous cell carcinoma; LHPP; Tumor suppressor gene; Tumor immune microenvironment; Chemotherapeutic sensitivity; Prognostic marker

CITE THIS PAPER

ZhiGang Zhai, Yuan Fang, ZhenYu Xue, Jian Guo, Xiang Tang. Expression and clinical significance of LHPP in esophageal squamous cell carcinoma. Journal of Pharmaceutical and Medical Research. 2026, 8(1): 37-46. DOI: https://doi.org/10.61784/jpmr3065.

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