Prognostic Value of GPNMB, EGFR, p-PI3K, and Ki-67 in Patients with Esophageal Squamous Cell Carcinoma

Background GPNMB is a newly discovered tumour-promoting factor that may promote tumour cell progression by activating the PI3K/AKT pathway by EGFR. However, there are insufficient studies about GPNMB in ESCC. This study investigated the relationship between GPNMB and EGFR/PI3K pathway genes in ESCC. Methods The expression levels of GPNMB, EGFR, p-PI3K, and Ki-67 were examined using immunohistochemistry. Statistical analysis was done by SPSS 22.0 and R. Results GPNMB mRNA expression is higher in ESCC compared with paracancerous tissues. The expression of EGFR, PIK3CA, PIK3CB, and AKT1 was increased in GPNMB upregulated samples. GPNMB expression was positively correlated with EGFR, p-PI3K, and Ki-67 expression. GPNMB was expressed higher in the AJCC III stage, lymph node metastasis, and moderately poorly differentiated patients. EGFR was higher expressed in patients with vascular invasion; p-PI3K expression in Kazak was higher than that in Han; Ki-67 expression was higher in tumour size ≥ 3 cm. Patients with high expression of GPNMB, p-PI3K, and Ki-67 had worse OS. p-PI3K, Ki-67, nerve invasion, and lymphatic metastasis were independent risk factors, and postoperative adjuvant therapy was a protective factor in ESCC. Conclusion As a tumour-promoting factor, GPNMB is expected to be a potential target for ESCC.

[1]  Z. Dong,et al.  PI3K/Akt/mTOR Signaling Pathway: Role in Esophageal Squamous Cell Carcinoma, Regulatory Mechanisms and Opportunities for Targeted Therapy , 2022, Frontiers in Oncology.

[2]  J. Ajani,et al.  Esophageal cancer: emerging therapeutics , 2022, Expert opinion on therapeutic targets.

[3]  Yamei Chen,et al.  Activation of PI3K/AKT Pathway Is a Potential Mechanism of Treatment Resistance in Small Cell Lung Cancer , 2021, Clinical Cancer Research.

[4]  Tianxiang Li,et al.  CYP2C8 Suppress Proliferation, Migration, Invasion and Sorafenib Resistance of Hepatocellular Carcinoma via PI3K/Akt/p27kip1 Axis , 2021, Journal of hepatocellular carcinoma.

[5]  Jingming Zhang,et al.  Adaptive resistance in tumors to anti-PD-1 therapy through re-immunosuppression by upregulation of GPNMB expression. , 2021, International immunopharmacology.

[6]  Lei Jin,et al.  Visualization of endogenous p27 and Ki67 reveals the importance of a c-Myc-driven metabolic switch in promoting survival of quiescent cancer cells , 2021, Theranostics.

[7]  Xu Zhang,et al.  Comparative genomic analysis of esophageal squamous cell carcinoma and adenocarcinoma: New opportunities towards molecularly targeted therapy , 2021, Acta pharmaceutica Sinica. B.

[8]  Hiroyuki Suzuki,et al.  Glycoprotein non–metastatic melanoma protein B functions with growth factor signaling to induce tumorigenesis through its serine phosphorylation , 2021, Cancer science.

[9]  Chun-Yu Liu,et al.  Expression pattern and prognostic impact of glycoprotein non-metastatic B (GPNMB) in triple-negative breast cancer , 2021, Scientific Reports.

[10]  C. Caldas,et al.  PI3K activation promotes resistance to eribulin in HER2-negative breast cancer , 2021, British Journal of Cancer.

[11]  Szu-Hua Pan,et al.  N‐glycosylated GPNMB ligand independently activates mutated EGFR signaling and promotes metastasis in NSCLC , 2021, Cancer science.

[12]  Wei Tang,et al.  Evaluation of the Therapeutic Effect of Adjuvant Transcatheter Arterial Chemoembolization Based on Ki67 After Hepatocellular Carcinoma Surgery , 2021, Frontiers in Oncology.

[13]  J. Yun,et al.  HOXC10 upregulation confers resistance to chemoradiotherapy in ESCC tumor cells and predicts poor prognosis , 2020, Oncogene.

[14]  J. Sehouli,et al.  Ki67 expression as a predictor of chemotherapy outcome in low-grade serous ovarian cancer , 2020, International Journal of Gynecological Cancer.

[15]  J. Kalmar,et al.  Expression of cornulin in oral premalignant lesions. , 2019, Oral surgery, oral medicine, oral pathology and oral radiology.

[16]  Xiaohua Douglas Zhang,et al.  Multicellular gene network analysis identifies a macrophage-related gene signature predictive of therapeutic response and prognosis of gliomas , 2019, Journal of Translational Medicine.

[17]  Zhijun Sun,et al.  High expression of GPNMB predicts poor prognosis in head and neck squamous cell carcinoma. , 2019, Histology and histopathology.

[18]  P. Philip,et al.  Comparative Molecular Analyses of Esophageal Squamous Cell Carcinoma, Esophageal Adenocarcinoma, and Gastric Adenocarcinoma. , 2018, The oncologist.

[19]  Xiaoqian Zhou,et al.  GPNMB silencing suppresses the proliferation and metastasis of osteosarcoma cells by blocking the PI3K/Akt/mTOR signaling pathway. , 2018, Oncology reports.

[20]  Hong-yan Cheng,et al.  Overexpression of GPNMB predicts an unfavorable outcome of epithelial ovarian cancer , 2018, Archives of Gynecology and Obstetrics.

[21]  Yang Zhang,et al.  Correlations of ALDH2 rs671 and C12orf30 rs4767364 polymorphisms with increased risk and prognosis of esophageal squamous cell carcinoma in the Kazak and Han populations in Xinjiang province , 2018, Journal of clinical laboratory analysis.

[22]  A. Avan,et al.  The Therapeutic Potential of PI3K/Akt/mTOR Inhibitors in Breast Cancer: Rational and Progress , 2018, Journal of cellular biochemistry.

[23]  A. Avan,et al.  The Potential Value of the PI3K/Akt/mTOR Signaling Pathway for Assessing Prognosis in Cervical Cancer and as a Target for Therapy , 2017, Journal of cellular biochemistry.

[24]  S. Hammes,et al.  Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB) and Cancer: A Novel Potential Therapeutic Target , 2017, Steroids.

[25]  C. Heldin,et al.  The transcription factor MAFK induces EMT and malignant progression of triple-negative breast cancer cells through its target GPNMB , 2017, Science Signaling.

[26]  Hong Li,et al.  Racial Differences in Esophageal Squamous Cell Carcinoma: Incidence and Molecular Features , 2017, BioMed research international.

[27]  C. Qin,et al.  Knocking down glycoprotein nonmetastatic melanoma protein B suppresses the proliferation, migration, and invasion in bladder cancer cells , 2017, Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine.

[28]  Peijun Liu,et al.  Glycoprotein non-metastaticmelanoma protein B promotes glioma motility and angiogenesis through the Wnt/β-catenin signaling pathway , 2016, Experimental biology and medicine.

[29]  Liqun Yu,et al.  Anticipatory activation of the unfolded protein response by epidermal growth factor is required for immediate early gene expression and cell proliferation , 2016, Molecular and Cellular Endocrinology.

[30]  Wei Zhang,et al.  iTRAQ-based quantitative proteomic analysis of esophageal squamous cell carcinoma , 2016, Tumor Biology.

[31]  Leng Han,et al.  The LINK-A lncRNA Activates Normoxic HIF1α Signaling in Triple-negative Breast Cancer , 2016, Nature Cell Biology.

[32]  Judith Cave,et al.  The assessment of Ki-67 as a prognostic marker in neuroendocrine tumours: a systematic review and meta-analysis , 2015, Journal of Clinical Pathology.

[33]  R. Cardiff,et al.  "Score the Core" Web-based pathologist training tool improves the accuracy of breast cancer IHC4 scoring. , 2015, Human pathology.

[34]  R. Rocha,et al.  Immunohistochemical assessment of PTEN in vulvar cancer: best practices for tissue staining, evaluation, and clinical association. , 2015, Methods.

[35]  P. Siegel,et al.  GPNMB cooperates with neuropilin-1 to promote mammary tumor growth and engages integrin α5β1 for efficient breast cancer metastasis , 2015, Oncogene.

[36]  Q. Zhan,et al.  A Panel of Overexpressed Proteins for Prognosis in Esophageal Squamous Cell Carcinoma , 2014, PloS one.

[37]  Xin He,et al.  Ki-67 is a valuable prognostic predictor of lymphoma but its utility varies in lymphoma subtypes: evidence from a systematic meta-analysis , 2014, BMC Cancer.

[38]  I. Sheyhidin,et al.  Association of the plasma riboflavin levels and riboflavin transporter (C20orf54) gene statuses in Kazak esophageal squamous cell carcinoma patients , 2013, Molecular Biology Reports.

[39]  M. Sekar,et al.  Modulation of Epidermal Growth Factor stimulated ERK phosphorylation and cell motility by inositol trisphosphate kinase , 2010, Journal of pharmaceutical sciences and pharmacology.

[40]  D. Mutch,et al.  Immunohistochemical analyses of estrogen receptor in endometrial adenocarcinoma using a monoclonal antibody. , 1986, Cancer research.

[41]  H. Parkman,et al.  Clinical and translational advances in esophageal squamous cell carcinoma. , 2019, Advances in cancer research.

[42]  C. Angelopoulos ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY ORAL Radiology , 2014 .

[43]  S. Law,et al.  The current management of esophageal cancer. , 2007, Advances in surgery.