Identification and Validation of Chromobox Family Members as Potential Prognostic Biomarkers and Therapeutic Targets for Human Esophageal Cancer

Abstract

Background: Chromobox family proteins (CBXs) are vital components of epigenetic regulation complexes and transcriptionally inhibit target genes by modifying the chromatin. Accumulating evidence indicates that CBXs are involved in the initiation and progression of multiple malignancies. However, the expression, function, and clinical relevance such as the prognostic and diagnostic values of different CBXs in esophageal carcinoma (ESCA) are still unclear.Methods: We applied Oncomine, TCGA, GEO, GEPIA, UALCAN, Kaplan–Meier plotter, cBioPortal, Metascape, and TIMER to investigate the roles of CBX family members in ESCA. Additionally, quantitative real-time PCR (RT-PCR), western blot, and immunofluorescence were used to verify the expression of CBX family members in ESCA clinical samples.Results: Compared with normal tissues, the mRNA expression levels of CBX1/3/8 were significantly increased in ESCA, whereas CBX7 mRNA expression was reduced in both the TCGA cohort and GEO cohort. In the TCGA cohort, ROC curves suggested that CBX1/2/3/4/8 had great diagnostic value in ESCA, and the AUCs were above 0.9. Furthermore, upregulation of CBX1/3/8 and downregulation of CBX7 were closely related to the clinicopathological parameters in ESCA patients, such as tumor grades, tumor nodal metastasis status, and TP53 mutation status. The survival analysis indicated that higher CBX1/3/8 mRNA expressions and lower CBX7 expression suggested an unfavorable prognosis in ESCA. High genetic change rate (52%) of CBXs was found in ESCA patients. Functions and pathways of mutations in CBXs and their 50 frequently altered neighbor genes in ESCA patients were investigated; the results showed that DNA repair and DNA replication were correlated to CBX alterations. Moreover, we found a significant correlation between the expression level of CBX family members and the infiltration of immune cells in ESCA. Finally, we verified the expression of CBX family members in clinical samples and found the results were consistent with the databases.Conclusion: Our study implied that CBX1/3/7/8 are potential targets of precision therapy for ESCA patients and new biomarkers for the prognosis.

A Regulatory Network Analysis of the Importance of USP15 in Breast Cancer Metastasis and Prognosis

“…In this study, we found that USP15 was highly expressed in breast cancer by searching the TCGA databases [ 32 , 54 ]. Then by searching the bioinformatics database UALCAN, GEPAI, Kaplan-Meier we.…”

Mining Transcriptomic Data to Uncover the Association between CBX Family Members and Cancer Stemness

“…Nowadays, it is well-established that the epigenetic dysregulation accelerates tumorigenesis, and at least partially, facilitates cancer stemness. Several reports suggest, that CBX family members possess the potential to become druggable targets in distinct tumor types, including breast, lung, ovarian, esophageal, and colon cancer [ 11 , 66 , 67 , 68 , 69 ]. However, these reports do not raise the question of therapeutic targeting of the stem cell-like phenotype of solid tumors and do not prove the engagement of CBX family members in molecular mechanism modulating cancer stemness.…”

Chromobox proteins in cancer: Multifaceted functions and strategies for modulation (Review)

“…Compared with normal tissues or paracancerous tissues, the expression of all or some of the CBX1/2/3/4/5/8 members is upregulated in most cancer tissues, including glioma (67-69), tongue squamous cell carcinoma (TSCC) (70), head and neck squamous cell carcinoma (HNSCC) (71), breast cancer (BC) (15,(72)(73)(74)(75)(76)(77)(78)(79)(80), non-small cell lung cancer (NSCLC) (81)(82)(83)(84)(85), esophageal cancer (EC) (86)(87)(88)(89)(90), gastric cancer (GC) (91)(92)(93)(94)(95)(96)(97)(98), pancreatic adenocarcinoma (PAAD) (99,100), colorectal cancer (CRC) (101-104), urinary bladder cancer (UBC) (105), sarcoma (106) and osteosarcoma (107,108). As a tumor suppressor, CBX7 is expressed at low levels in most tumors, such as glioma, HNSCC (71), EC (87,88), GC (93)(94)(95)(96)(97)(98), PAAD (109), CRC (103,104), clear cell renal cell carcinoma (ccRCC) …”

“…CBX3 is a poor prognostic factor in as many as 13 tumor types (67,69-71,80 ,81,84,86-88,101,106,110,111,114,116,122,123). CBX4 is of prognostic value in BC (76,80), LUAD (85), EC (86)(87)(88), GC (92,94,95,98), HCC (11) and ccRCC (110). In addition, patients with BC (80), LUAD (84), GC (94)(95)(96)(97)(98), CRC (103), sarcoma (106), SKCM (113) with upregulated CBX5 and HNSCC (71) and ccRCC (110) with downregulated CBX5 have poor prognosis.…”

“…CBX7 acts as a tumor suppressor in glioma (68), BC (15,77), LUAD (83,84,125), HCC (114,119), PAAD (99,109), ccRCC (110), CCA (112), sarcoma (106) and SKCM (113). When the expression of CBX7 is low, the OS of patients is shorter, but its relationship to survival in EC (86)(87)(88) and GC (94-98) is controversial. High expression of CBX8 in patients with glioma (67), BC (79), HCC (120,121), CRC (102), ccRCC (110) and UBC (105) lead to unfavorable prognosis, but patients with LUAD (84) with low CBX8 expression exhibit a shorter OS.…”