The presence of tumor heterogeneity leads to reduced therapeutic efficacy and poor prognostic outcomes. Despite the gradual improvement in the understanding of tumor cell subpopulations with the advent of novel technologies such as single-cell sequencing, the field of clinical oncology remains slow. Therefore, it is of great importance to effectively accelerate the pace of clinical translation through the search for new tumor marker.
Some research progress has been made on CDKN3 at the present time, and CDKN3 has been found to have a role in the regulation of cell cycle progression, severe COVID-19, female reproductive toxicity, vascular endothelial cell injury, control of mitosis, and promotion of adipocyte proliferation. There have been studies on how CDKN3 regulates the progression of a single tumor, which indirectly demonstrates the possibility of CDKN3 acting as a target for tumor markers. However, there is a lack of research in this area to analyse whether CDKN3 is suitable as a tumor marker or not from a macroscopic overall perspective.
Here, we performed a pan-cancer analysis using bioinformatics data. In TCGA-GTEx samples, TCGA samples, and TCGA paired samples, we examined the differential expression of CDKN3 in normal and tumor tissues of several organs.We found significant variations in the expression of CDKN3 between tumor and normal tissues. With the exception of THCA, we confirmed that most tumor tissues had higher CDKN3 expression than paired normal tissues. However, inconsistent results were obtained. For example, the conclusions obtained for TCGA_GTEx and THCA were diametrically opposed to those for TCGA, and we speculate that this may be due to differences in we speculate that this may be due to differences in the sample size of the control group. Therefore, in order to obtain more accurate conclusions, we suggest increasing the sample size of the control group.
To date, there is no overall assessment of the prognostic value of CDKN3 in various cancers. In this study, we demonstrated the multifaceted prognostic impact of CDKN3 overexpression on tumor OS based on TCGA and GEO databases. Our study showed that cancer patients with elevated CDKN3 expression had poorer OS, DSS, DFI, and PFI, especially in ACC, BLCA, KIRC, KIRP, LGG, LIHC, MESO, PAAD, and UVM. It has been confirmed that high expression of CDKN3 promotes proliferation and metastasis in renal cell carcinoma25. while a bioinformatics-based key gene screen revealed that increased levels of CDKN3 lead to poor prognosis in hepatocellular carcinoma26. while no relevant studies have been conducted on CDKN3 in bladder tumors, multiple myeloma, neuroendocrine tumors and melanoma. According to our findings, CDKN3 also plays a very important role in the above mentioned tumors, therefore, future studies engaging in these kinds of tumors can continue to explore the role played by CDKN3 in them.
Interestingly, we found that CDKN3 and immune cells also have some connections. In the tumor microenvironment, immune cells, which are the soil, have an extremely important role for tumors. Our analysis reflects that CDKN3 has some correlation with CD4 + T cells, fibroblasts, macrophages and endothelial cells. Interestingly, the level of CDKN3 and macrophage infiltration varies in different cancer types. Therefore, we grouped them according to the level of expressed CDKN3 content. By grouping, we tried to explore the crosstalk between CDKN3, immune cells, and tumor prognosis. Based on the findings, we found a strong association between CDKN3 and the degree of immune cell infiltration. In turn, a high level of immune cell infiltration implied a poor tumor prognosis. Therefore, we speculate that high levels of CDKN3 may interfere with the prognosis of tumor patients by affecting immune cells and thereby. This is consistent with the results of a number of studies that have been previously obtained 27,28.
And the link between CDKN3 and clinical prognosis is not limited to immune cells in the tumor microenvironment. In addition to correlating the prognosis of 17 tumors with CDKN3 expression as analysed by TCGA, we also found a correlation between CDKN3 expression in ACC, KIRC, KIRP and LIHC and tumor size. It is worth thinking whether CDKN3 is linked in some aspects of tumor cell renewal and proliferation? It was shown that miR-127-3p promotes the proliferation and metastasis of renal cell carcinoma through CDKN25. And ZNF677 was also shown to inhibit the progression of renal cell carcinoma through the transcription of N6-methyladenosine and CDKN29. CDKN3 was moreover demonstrated to be an independent prognostic factor contributing to the progression of nasopharyngeal carcinoma to advanced stages30. which is in line with our concluded. In addition to tumor progression, we also found that CDKN3 was associated with lymph node metastasis in six tumors. This result was similarly confirmed in oral cancer31. In summary, we can confirm that the presence of CDKN3 predicts a poor tumor prognosis. Therefore, the use of CDKN3 as a tumor therapeutic target would be of great importance. There have already been studies identifying CDKN3 as a core gene for colorectal cancer prognosis by transcriptomics 32, and in the future we believe that CDKN3 will have a broader research prospect.
In the current various researches targeting tumors, besides the immune microenvironment we mentioned above, and various common cell death modes (e.g. apoptosis, autophagy, etc.), there is nothing hotter than epigenetic modifications. And methylation modification has been a hot field for many scholars in it. Our study also found that the methylation expression level of CDKN3 in HNSC and TGCT tumor tissues was significantly lower than that in normal tissues.In addition, the methylation expression level of CDKN3 was significantly elevated in ESCA, KIRC, LUSC and PAAD tumor tissues. This proves that CDKN3 may have a positive association with methylation. So, is there an association between CDKN3 and methylation or not? It has been demonstrated that ZNF677 inhibits renal cell carcinoma progression through the transcription of N6-methyladenosine and CDKN329. It has also been shown that modulation of neuroblastoma cell proliferation can alter the methylation of the promoter region of the CDKN3 gene33. Interestingly, CDKN3, as the RNA methylation-associated isoform of pancreatic cancer, has been demonstrated to be associated with immune infiltration28. This could enable us to determine whether CDKN3 is associated with methylation or not28, which can be linked to the correlation we elaborated in the previous paragraph. This is more reflective of the fact that in the tumor microenvironment, the exchange of information between cells is presented as a kind of meshwork in which CDKN3 plays a very crucial role.
Through the analysis in this paper, we found that CDKN3 has a strong connection with P53 and PI3K-AKT pathway, which is also confirmed 34,35 in related studies. However, we found that the NOTCH signalling pathway is also linked to CDKN3 through our study, but this has not been confirmed in relevant studies yet. It is worth thinking why no current studies focus on this signalling pathway? After all, the NOTCH signalling pathway has been shown to be a critical hub for both maintaining tumor cell stemness and causing DNA mutations. Is it because the link between NOTCH and CDKN3 is not as strong as we have analysed, or is it because of the number of samples, the type of tumor, or statistical errors that have led to a bottleneck in the relevant studies? This is all a focus we can explore in the future.
In summary, this paper highlights the role played by CDKN3 in pan-cancer analyses. Through different analyses, we exemplify the feasibility of CDKN3 as a tumor marker. However, it is very unfortunate that, firstly, this paper did not verify the importance of CDKN3 by relevant experimental means, and secondly, in the future, we hope to have the opportunity to combine the information of single-cell sequencing libraries to classify tumor cells in a more detailed way. We believe that a more in-depth analysis of the connection between CDKN3 and the tumor microenvironment is of great significance for the targeted treatment of tumors.