Advances in hERG1 and LHR based targeting in neoplastic and preneoplastic conditions

In this work we studied the role of hERG1 potassium channel and the luteinizing hormone receptor (LHR) in neoplastic and preneoplastic conditions. The present thesis is divided into three parts (three chapters). The first part concerns the depth study of hERG1 channel in Barrett‟s esophagus (BE) and its role during the progression to esophageal adenocarcinoma (EA), in order to (a) confirm hERG1 expression in a large cohort of BE patients (larger than the cohort studied in Lastraioli E et al 2006), (b) evaluate hERG1 expression during BE progression to esophageal dysplasia and EA. To deepen this topic and to better study the biology of hERG1 in BE, we developed three different mouse models of BE. Such models will be useful also to evaluatetherapeutic interventions and pharmacological tests. This study was also aimed at testing the possibility of considering hERG1 as a marker of BE progression to be further exploited for BE surveillance screening protocols. The second part of the present thesis was aimed at studying the effects of LH over-expression induction in the endometrium in vivo. For this purpose we generated a transgenic mouse model over-expressing hLHR in the reproductive tract with the aim of determining whether: (a) LH/hCG-R over-expression is capable of inducing the development of Endometrial Cancer (EC) per se. (b) LHR over-expression in endometrial cells is might be responsible of a more aggressive behaviour of differentiated EC cells. This model could be a useful model not only for deciphering the genetic basis of EC development, but also for developing and testing novel therapeutic options in preclinical studies. In the last part of the thesis we evaluated the expression levels of LHR and two ion channels, such as hERG1 and KCNA7, in a cohorts of EC patients, in order to search for associations between the expression of the two genes and a number of co-factors including clinical and pathological parameters. We have chosen to study LHR because it is proven to be involved in EC invasion and metastatic spread. As concerning hERG1 it was chosen because it was previously found to be aberrantly expressed in a several human tumors, as endometrial cancer, among others. In addition, we also evaluated the mRNA levels of KCNA7 ion channel, supposed to be dysregulated in EC (Fortunato A., PhD thesis).