Clusterin (CLU) is a nearly ubiquitous multifunctional protein synthesized in different functionally divergent isoforms, sCLU and nCLU, playing a crucial role by keeping a balance between cell proliferation and death. Studying in vivo CLU expression we found a higher mRNA expression both in neoplastic and hyperplastic tissues in comparison to normal endometria; in particular, by RT-qPCR we demonstrated an increase of the specific sCLU isoform in the neoplastic and hyperplastic endometrial diseases. On the contrary, no CLU increase was detected at the protein level. The CLU gene transcriptional activity was upregulated in the hyperplastic and neoplastic tissues, indicating the existence of a fine post-trans-criptional regulation of CLU expression possibly responsible for the protein decrease in the malignant disease. A specific CLU immunoreactivity was present in all the endometrial glandular cells in comparison to the other cellular compartments where CLU immunoreactivity was lower or absent. In conclusion, our results suggest the existence of a complex regulatory mechanism of CLU gene expression during the progression from normal to malignant cells, possibly contributing to endometrial carcinogenesis. Moreover, the specific alteration of the sCLU:nCLU ratio associated with the pathological stage, suggests a possible usage of CLU as molecular biomarker for the diagnosis/prognosis of endometrial proliferative diseases.

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BackgroundClusterin (CLU) is a ubiquitous multifunctional factor involved in neoplastic transformation. The CLU transcript variants and protein forms play a crucial role in balancing cells proliferation and death.MethodsWe investigated the regulation of CLU transcript variants expression in an in vivo model system consisting of both neoplastic tissues and fine needle aspiration biopsy (FNAB) samples isolated from patients undergoing thyroidectomy.ResultsThe immunohistochemical analyses showed an overall CLU up-regulation in papillary carcinoma. A specific CLU2 transcript variant increase was registered using qPCR in papillary carcinomas while CLU1 decreased. In addition, the analysis of CLU transcripts expression level showed an increase of the CLU2 transcript in the TIR 3 patients with histologically confirmed thyroid cancer.ConclusionsOur results suggest the existence of a specific alteration of CLU2:CLU1 ratio towards CLU2, thus providing the first circumstantial evidence for the potential use of CLU transcript variants as effective biomarkers for a more accurate assessment of the so called “indeterminate” thyroid nodules.

Abstract. The ß1C integrin is an alternatively spliced variant of the ß1 integrin subfamily that at variance with its wildtype counterpart, i.e., the ß1A integrin, inhibits cell proliferation in prostate cancer cells. We have recently shown that transcriptional, translational and post-translational processes contribute to the selective loss of ß1C integrin during prostate malignant transformation. Here, we investigated whether androgen deprivation therapy (ADT) may affect ß1C mRNA expression in prostate cancer. Neoplastic prostates were obtained from patients undergoing radical prostatectomy who had received neoadjuvant ADT. The ß1C mRNA level was measured by Northern hybridization experiments and compared to normal prostates obtained from patients who underwent radical cystoprostatectomy for bladder cancer. Furthermore, the ß1C integrin gene transcriptional activity was measured by nuclear Run-on assays. We found an increase of ß1C mRNA expression (208±11%; p<0,01) in patients who received ADT in comparison to those who did not. Furthermore, we demonstrated an increase of gene transcriptional activity (360±10%; p<0,01) possibly partially or completely responsible for the regulation of the ß1C integrin mRNA levels. Short-term administration of ADT seems to interfere with ß1C integrin expression, suggesting the existence of androgen-mediated pathways involving ß1C. Precise characterization of the mechanisms that regulate the expression of this factor in cancer cells will provide further insight into the molecular mechanisms involved in tumor progression and possibly contribute to the identification of molecular targets for the development of new therapeutic strategies.