The role of PIAS3, p-STAT3 and ALR in colorectal cancer: new translational molecular features for an old disease.

Objective: Human colorectal cancer (CRC) is characterized by a sequence of biological events that determine its induction and progression. Gut microbiota has an important role in this multistep model of carcinogenesis, as well as constitutive activation of Signal Transducer and Activator Factors 3 (p-STAT3) and Protein Inhibitor of Activated STAT3 (PIAS3), which negatively controls STAT3. It has been reported that a liver growth factor, the Augmenter of Liver Regeneration (ALR), an anti-apoptotic, anti-metastatic factor, exerts protective/cell survival and anti-metastatic activities and has been detected highly expressed in neoplastic cells.
Patients and Methods: To evaluate, by immunohistochemistry, p-STAT3, PIAS3 and ALR expression in neoplastic human tissues from CRC patients, grouping the data in accordance with the histological alterations (G1, G2 and G3) and metastasis presence. Western blot (WB) analysis of ALR was also determined in neoplastic and surrounding tissues. Finally, cell proliferation (Ki-67) and apoptosis (Bcl-2) were determined.
Results: Colon cancer tissue samples showed: (1) ALR and p-STAT3 strongly over-expression in 100% of G1 tissue samples, reducing in G2 and G3 tissue samples; (2) PIAS3 immunological determination was poorly expressed in G1 tissue samples and highly expressed in the 100% of colorectal tissues from group G2 and G3. Ki-67 progressively increases with the importance of the anatomic-pathological alterations and Bcl-2 resulted higher in G3 tissue samples compared to G1 neoplastic tissues. WB data evidenced, in neoplastic tissues, compared to the tumour-surrounding tissues, ALR over-expressed in G1 neoplastic tissues and down-expressed in G3 neoplastic tissues.
Conclusions: Our data demonstrate a different dynamism of the investigated factors in relation to the severity of CRC histological findings. We hypothesize that the positive expression of ALR and p-STAT3 in the neoplastic tissue samples from CRC G1 group, associated to the absence of PIAS3, could be useful marker to identify an early stage of the disease. Based on these data and on our previous studies on gut microbiota in precancerous intestinal lesions, we are confident that, after microbial priming, a cascade of molecular events is started. So, the detectable molecules acting in these initial steps should be considered for the study of CRC progression and therapy.