Prognostic diagnosis is the key to estimate the recurrence risk of CRC patients after therapeutic tumor excision. Today, the prognosis of patients is mainly based on cancer stage, tumor metastasis based on magnetic resonance imaging and/or positron emission tomography, and other markers,such as histopathological grade, gene stability and expression level.[13, 15, 19, 36] Once the lymphatic metastasis or nerve infiltration signs were detected, the patient have been already in a high-risk state. From the perspective of tissues, cells in stable regions and highly invasive regions in cancer tissues have different activated gene groups. Yet, unless specific sample is selected, genomic, transcriptome, and proteome data are difficult to reflect this characteristic. In theory, the cancer tissues of patients who are prone to relapse may contain more abundant such malignant cells. Therefore, we believed that genes, proteins and other biomarkers components related to CRC duplication can be found more effectively in this type of patient tissue.
In this study, we used proteomics and bioinformatics methods to find DEPs from surgical tissues of relapsed stage II CRC patients. As a result, we found 136 DEPs which may closely relate to the recurrence of CRC patients after surgery excision. Especially, through patient survival retrospective, biological information analysis, and reported studies, it can be shown that certain genes/proteins are closely related to cancer cell energy metabolism, proliferation, metastasis, invasion and immune escape. Therefore, we think there may contain protein biomarkers for poor prognosis of CRC patients in the DEPs.
During cancers development, the highly invasive fronts play important roles for recurrence. These areas contain a large number of pluripotent tumor stem cells, which is responsible for rapid growth, invasion and distant metastasis of the cancer. Several biomarkers have been focused on this area and have shown good clinical effects.
In addition, the regions of differentiated cancer tissues are often separated by connective tissue. Based on connective tissue, accompanied with the entry of blood vessels and nerve tissues, the differentiated areas enter a relatively stable state. Thus, these areas are not easily transformed into highly invasive state, and the patient will not deteriorate due to this type of tumor tissue in a short time. Another case between the differentiated areas is poorly differentiated cells, which are scattered or distributed in a dense state with high invasiveness and proliferation. These cells are also an important factor in the distant metastasis, and this corresponding region often become a key factor for cancer recurrence. Therefore, we think it meaning to pay attention to the biological characteristics of the pathological tissues, especially genes which have positive guiding value for prognosis.
MEIS3, is mainly expressed in invasive fronts and the spaces between differentiation areas of CRC tissues, forming scattered or dense nuclear staining characteristic. The distribution range of these kinds of cells have positively correlated with the MEIS3 expression level. At the molecular level, we confirmed that MEIS3 may promote the migration and invasion of tumor cells by promoting the LAMB1 expression. Therefore, the high expression of MEIS3 is not only significantly related to the clinical stage of CRC patients, but also hinting a high-risk for CRC metastasis and recurrence. The 5-year DFS of clinical stage II patients with high MEIS3 expression was comparable to the overall level of stage III patients. And 5-year DFS expectation of the corresponding stage III patients with high MEIS3 expression was approximately closer to the overall level of the stage IV patients. Especially when combined with gender, the differentiation was further enlarged, and the risk of male was greater than that of female.
In the therapy of patients with advanced CRC, adjuvant chemotherapy and radiotherapy have played an important role in clinical practice, and the expected 5-year DFS rate has been significantly improved.[4, 19] However, due to the severely differentiated outcomes in stage II and III patients, it is controversial whether adjuvant radiotherapy and/or chemotherapy is needed for these patients. Ultimately, the benefits of these patients from modern medicine are far less than advanced stage patients.[5, 39] Here, stage II and III patients with high expression of MEIS3, especially males, had poor prognosis. It is need to treat these patients according the therapeutic measure of high-risk patients to improve their survival rate and life quality.
Of course, we also found that MEIS3 can promote the transformation through activation of LAMB1 which play crucial roles in Epithelial-Mesenchymal Transition,[38, 40] yet, it is still a superficial result. We don't know the specific genes involved in this process, nor the specific regulation process mode between these genes. Therefore, further research is needed to identify the specific molecular mechanism of MEIS3 in determining the fate of tumor/cancer cells.
In addition, we need to study the feasibility of MEIS3 as a biomarker of poor prognosis with larger retrospective CRC patients groups, especially in patients with concurrent therapy and follow-up, before applied in clinical therapy for improving their survival rate and life quality.