Herein, the authors investigated the global expression status and prospective transcriptional regulation mechanisms of PTTG1 in BLCA. PTTG1 was significantly over-expressed in 1037 BLCA tissue samples and showed a strong ability in distinguishing BLCA tissue from normal bladder tissue. High PTTG1 expression showed increased antitumor activity in BLCA tissues, with elevated infiltration levels of NK, cytotoxic lymphocytes, and monocytic lineage cells. More importantly, the authors preliminarily identified the positive transcriptional activity between PTTG1 and CHEK2, OCIAD2, UBE2L3, and ZNF367.
The over-expression trend of PTTG1 in BLCA were certified using multi-faceted data sets. To probe the comprehensive expression status of PTTG1 in BLCA tissues, we made full use of the in-house immunohistochemistry data and external expression matrices, and a total of 1037 BLCA tissue specimens as well as 127 normal bladder tissue specimens were integrated. Consistently, we observed the increased expression trends of PTTG1 at both tissue and cell levels. Moreover, PTTG1 mRNA may be a strong distinguishing biomarker for BLCA and its over-expression could presage poor OS condition in BLCA patients. In summary, it is suggested that PTTG1 mRNA over-expression may operate as a cancer-promoting factor and could have the potential to be a predictor of poor prognosis in BLCA.
Furthermore, the potential PTTG1 activity in BLCA TME was investigated. As is well known, the abnormal TME is a hotbed for cancer initiation and progression, where immune and stromal cells take an important part. Among them, mononuclear phagocyte system constitute an essential part of human tumor immunity; and cytotoxic lymphocytes, together with NK cells, constitute an important defense line in anti-tumor immunity . Previous study has reported that higher PTTG1 expression could be found in the CD4+ and CD8+ T lymphocytes of adult T-cell leukemia patients than that of healthy subjects, which implied an intimate association between PTTG1 and lymphocytes. According to the Rostyslav Stoika et al., the mRNA abundance of PTTG1 corresponded to the increase in S-phase cells during the activation of T lymphocytes, which suggested that PTTG1 expression may follow the cell cycling patterns in T cells. In the present study, a high PTTG1 mRNA expression group was shown to be enriched with NK, cytotoxic lymphocyte, and monocyte lineage cells in BLCA patients. Furthermore, the immune score was significantly higher in high PTTG1 mRNA expression group than that in low PTTG1 mRNA expression group in BLCA tissues. Moreover, there was a positive association between the mRNA expression levels of PTTG1 and dendritic cell infiltration levels, which reflexed the antigen-presenting activity in BLCA tissue. In this setting, we inferred that PTTG1 may serve as an oncogene and possess immunogenicity in BLCA, which has the potential to be designed as mRNA vaccine in the future. Intriguingly, it has been shown that SP17/AKAP4/PTTG1 could induce an immunogenic response in non-small cell lung cancer patients. Moreover, higher expression level of PTTG1 correlated to immune checkpoint response in papillary renal cell carcinoma cohort. Such evidences pointed out that PTTG1 may be a promising immunotherapeutic target for BLCA patients. More experiments are required to be performed to promote the researches of novel cancer vaccine for BLCA in the future study.
The prospective transcriptional mechanisms of PTTG1 were preliminarily portrayed in BLCA. CHEK2, OCIAD2, UBE2L3, and ZNF367 were predicted to be four positive transcriptional targets of PTTG1 in BLCA. Multiple studies have reported these four transcriptional targets of PTTG1 in tumor tissue. For instance, researchers performed immunohistochemical staining in BLCA samples and showed that CHEK2 protein expression surpassed 11 percent in 115 out of 126 BLCA tissue specimens. Additionally, CHEK2 mutation was reported to be a risk factor for the recurrence of BLCA. Similarly, OCIAD2, UBE2L3, and ZNF367 also displayed intimate association with cancer development. In previous function assays, OCIAD2 was showed to be essential for the activation of signal transducer and activator of transcription 3 and cell migration, which suggested that OCIAD2 may contribute to the metastasis of cancer cells. In liver cancer and oral squamous cell carcinoma, UBE2L3 was reported to be an important pro-tumorigenic factor in carcinogenesis [37, 38] and may be a potential treatment target for hepatocellular carcinoma. Moreover, ZNF367 could induce the transcriptional activation of kinesin family member 15, leading to elevated cell viability and invasion ability in breast cancer cells. Nonetheless, the biological functions of OCIAD2, UBE2L3, and ZNF367 in BLCA remained obscure, and more experimental exploration are required to understand their roles in BLCA development. Generally, the predicted transcriptional mechanism results supported the previous speculation that over-expression of PTTG1 seemed to be associated with the initiation and development of BLCA.
The present study has numerous highlights. Using integrated in-house immunohistochemical data from our institution, TCGA, and GEO datasets, we fully discovered PTTG1 over-expression in BLCA and its potential as a biomarker and prognostic value. The limitations of this study could not be overlooked. First, despite the fact that we combined datasets from multiple sources, the high-degree heterogeneity could not be eliminated by the randomized effect model; second, the total sample size was limited, and more experimental studies must be carried out in the future to demonstrate our findings and clarify the specific mechanism of PTTG1 in the development and progression of BLCA.