PLAC8 is a protein containing 115amino acids with abundant cysteine , firstdiscovered to show high expression within mouse placenta . According to our results, PLAC8 inhibits the apoptosis of BRCA through the activation of the PI3K/AKT/NF-κB signal transduction pathway. PLAC8 plays a vital role as an oncogene or tumor suppressor gene during cancer development . Nevertheless, comprehensive study on the association between PLAC8 level and immune infiltration, T cell activity, andthe pan-cancer prognosis is limited. Our study revealed that PLAC8 level was associated withthe prognostic outcome of various malignancies, especially BRCA, by analyzing massive tumor specimens derived from a series of large public databases. Besides, PLAC8 expression was positively related to the degree of immune infiltration within BRCA. The analysis on gene expression correlations for T cells robustly validated that PLAC8 significantly interactedwith numerous functional T cells within BRCA, particularly the exhausted T cells. Therefore, PLAC8 provides new directions as a possible prognostic biomarker for BRCA for exploiting the association of PLAC8 with T cell function and immune infiltration.
Our study comprehensively investigated PLAC8 expression and systematic prognostic signature in pan-cancers based on several public datasets in TIMER and 33 malignancies from TCGA-based GEPIA2, which revealed differential PLAC8 expression between cancerous and normal tissue in various malignancies. PLAC8 expression increased in HNSC-HPVpos, KIRC, and KIRP compared to normal tissue in the TIMER database. However, several datasets revealed lower PLAC8 expression in BRCA, CHOL, COAD, HNSC, KICH, LIHC, LUAD, LUSC, PRAD, READ, SKCM. The varied PLAC8 level in various malignancies in different databases might be due to variations in the data collection and intrinsic biological properties. However, a robust, consistent prognostic association of PLAC8 expression was found in these databases in BRCA. In PrognoScan, the PLAC8 level was significantly related to survival inAML, skin cancer, and, particularly, breast cancer. Further analysis using GEPIA2 and KM Plotter suggested that down-regulation of PLAC8 predicted the dismal prognostic outcome of BRCA, LUSC, OV, STAD, CESC, SARC, SKCM, CHOL, LIHC, and LUSC. Moreover, PLAC8 expression significantly correlated with patient ER status – array, PR status – IHC, HER2 status – array, Intrinsic subtype, Grade, and Pietenpol subtype. Collectively, these outcomes indicated PLAC8 as a prognostic biomarker for BRCA.
Similarly, CancerSEA analysis indicated the involvement of PLAC8 in cancer metastasis and invasion. Further, PLAC8 was verified to inhibit BRCA apoptosis by activatingPI3K/AKT/NF-κB signal transduction pathway. PLAC8 may play a role as an oncogene or a tumor suppressor gene during cancer development . We, therefore, propose that PLAC8 could be a potential BRCA biomarker.
TISIDB-based assessment of the relationship of PLAC8 with the immune system revealed that it was significantly correlated with lymphocytes, immuno-inhibitors, immuno-stimulators, and MHC molecules. The T1-type chemokine epigenetic silencing was demonstrated as a new immune evasion mechanism within cancers, whereas epigenetic reprogramming facilitated theselective increase in the therapeutic efficacy in BRCA . Therefore, PLAC8 associated with the above immune molecules might be a novel target to investigate immune evasion in BRCA, likely to function as an immunotherapeutic target. BRCA is classified into various molecular subtypes. TISIDB database analysis revealed that PLAC8 expression was the highest in basal subtype, followed by the normal type, Her2, lumA, and lumB types. Varied PLAC8 levels were detected in distinct immune subtypes in BRCA, with the highest in the C2 type. The in-depth and comprehensive study on PLAC8 gene expression in diverse databases of BRCA and subtypes indicated the potent correlation of PLAC8 with immunological properties in the tumor microenvironment (TME).
Due to the strong impact of PLAC8 on the immune system and the remarkable prognostic significance in BRCA, we analyzed the association between PLAC8 and the degree of immune infiltration within BRCA. Consequently, higher PLAC8expression predicted a markedly increased degree of immune infiltration within diverse immune cell subsets, such as CD8 + T and B cells, particularly neutrophils, CD4 + T cells, andDCs, with a higher correlation degree. Additionally, B cell infiltration was significantly related to BRCA prognosis. Despite the insignificant effect of varied SCNA of PLAC8 on immune infiltration degree of B cells, neutrophils, and DCs in BRCA, our focus was on the tight correlation of PLAC8 with immune cells. Analysis of PLAC8 and immune cell gene markers further demonstrated that PLAC8 closely interacted with most immune cells and diverse functional T cells, including central memory T cells, effector, and exhausted T cells. T cell exhaustion is a main obstacle for inadequate anti-tumor immunity [43–45]; hence it is essential to abolish the progression of exhausted T cells. In our study, increased PLAC8 level was positively correlated to various critical genes of exhausted T cells, including PD-1, TIM-3, TIGIT, LAG3, and GZMB, presently therapeutic targets or participate in immunotherapy [46, 47].
Intriguingly, we revealed the dual roles of PLAC8. High PLAC8 level positively correlated with superior prognosis in various types of malignancies, including BRCA, and simultaneously triggered T cell exhaustion, leading to inadequate anti-tumor immunity. The underlying mechanism has been explained recently by several researchers. PLAC8 showeda positive effect on regulating the migration and invasion of trophoblasts by promoting Cdc42 and Rac1 activation . Therefore, PLAC8 plays a diverse role in normal immunity development and modulating TME, which requires identification in a specific stage.
To summarize, the present outcomes implicated PLAC8 as a prognostic biomarker in pan-cancers, particularly BRCA. Elevated PLAC8 expression is associated with a high immune infiltration degree in B cells, CD4 + T cells, Macrophages, DCs, neutrophils, CD8 + T cells, and most functional T cells. Despite its vital function in immunity development, PLAC8 is significantly related to T cell exhaustion and might promote T cell exhaustion in BRCA. Therefore, PLAC8 expression determination might assist in prognostic prediction. Besides, its modulation within exhausted T cells possibly could serve as the new approach for optimizingthe therapeutic effect of immunotherapy among BRCA cases.