It is well-known that CDKN1B is a tumor-inhibiting factor that encodes p27kip1, a cyclin-dependent kinase inhibitor[10]. The CDKN1B protein is associated with various cellular biological processes, such as gene transcription regulation, the cell cycle and cell apoptosis[29–31]. In addition, the CDKN1B-encoded protein also is responsible for cellular immunity, which is mainly reflected in its influence on the cycle progression of T lymphocytes[30–31]. The cell cycle, including the progression from G0 to G1 to S phase, and both positive and negative regulators both govern the proliferation of immune cells, including T cells that express CDKN1B [30]. CDKN1B is a major negative regulator of the cell cycle, and its degradation can promote the transition of CD8+ T cells from G1 to S phase after TCR stimulation[30–31]. It is still unknown whether CDKN1B has a role in the development of a number of cancers. Here, we firstly used the TCGA, CPTAC and GEO datasets to analyze molecular characteristics of gene expression and genetic alterations of CDKN1B.
CDKN1B is highly expressed in most of cancers, which was also confirmed in STAD and LIHC by IHC in our study. However, for different tumors, CDKN1B gene survival prognostic analysis data had reached different conclusions. In this study, the significant link between CDKN1B expression and the overall survival prognosis of KIRC, as well as the disease-free survival prognosis of CHOL, KIRC and UVM were also observed via the GEPIA2 tool. These findings suggested that CDKN1B was involved in the development of human cancers, which might be considered to be biomarker for the prognosis of cancers. Research is mounting that CDKN1B alterations are crucial in the development and prognosis of malignancies[32–33]. The samples from ovarian cancer, testicular cancer, and uterine carcinosarcoma revealed that "amplification" was the most prevalent kind of mutation. In prostate cancer, the "deep deletion" mutation type was more prevalent. According to earlier studies, a range of immune cells that infiltrate tumors are modulated by cancer-associated fibroblasts [33]. Combining the feature with the level of CDKN1B expression in various tumors, it was discovered that CDKN1B expression was significantly correlated with estimated infiltration values of cancer-associated fibroblasts from TCGA tumors, including CESC, COAD, HNSC, HNSC with negative human papillomavirus (HPV-)], LUAD, PAAD, STAD, and TGCT, but negatively correlated with GBM. These findings indicated a close connection between cancer types, CDKN1B, and cancer-associated fibroblasts.
The significance of CDKN1B in carcinogenesis is critical for cancer diagnosis and treatment. Six genes were chosen among the 100 CDKN1B-linked genes for scatter plot mapping, and the results, together with the heatmap data, demonstrated that they were positively correlated with CDKN1B expression. These data also revealed, by cross-analysis, that CCNT1 is a common member. Cyclin T1 (CCNT1) is a gene with 9 exons that can assemble into a complex of positive transcription elongation factor b (P-TEFb) and regulate a variety of biological processes, including transcription[34]. These inklings indicated that CCNT1 may be the focus of further research.
Our results indicated that the cell cycle and PI3K/Akt signal pathway were involved in CDKN1B’s effects on the tumorigenesis mechanism. A previous study showed that increased Skp2 activity in malignancies with RB1 deficiency or mutations suppressed CDKN1B expression and led to an unregulated cell cycle. Skp2 was a target for cancer treatment and was implicated in controlling CDKN1B expression[35]. Furthermore, several studies have demonstrated that osteosarcomas' overexpression of miR-802 impedes the PI3K/AKT pathway by targeting CDKN1B[36]. These findings might provide a potential role for human cancers in future research directions.
Using KIRC as an example, CDKN1B levels in malignant tissues increased than those in control, healthy tissues. Furthermore, in KIRC, a high prognosis for overall survival and DFS was linked to increased CDKN1B expressio. In addition, previous report had shown that FGF-2 could promote the proliferation of KIRC by regulating p27kip1[37]. Therefore, the pan-cancer study of CDKN1B can both widen research perspectives and support previous results. However, there are several limitations, particularly other independent cohort and in vitro or in vivo studies need be carried out to verify these results.