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  • br ABCC and ABCC in PDAC ducts which for

    2020-03-24


    ABCC3 and ABCC5, in PDAC ducts, which for ABCC3 correlated positively with the tumour grading (Konig et al., 2005). However, no study has so far reported the involvement of ABC transporters in PDAC development or identified their potential as pharmacological targets in PDAC.
    Here, we have demonstrated that the ABC transporter ABCC3 is a novel and key player in PDAC biology, playing an active role in its progression. We showed that ABCC3 is highly expressed in PDAC specimens and the available bioinformatic data concurs that its
    A. Adamska, et al. Advances in Biological Regulation xxx (xxxx) xxxx
    Table 1
    Expression of membrane ABCC3 in PDAC (n = 60) according to p53 IHC status.
    a Mean percent of positive tumour Pyocyanin ± Standard Error (SE). b Independent-sample t-test.
    expression correlates with poor prognosis for patients. We also showed that ABCC3 regulates PDAC cell proliferation in vitro and in vivo through the release of lysophosphatidylinositol (LPI), whose importance in PDAC progression we recently reported (Falasca and Ferro, 2016; Ferro et al., 2018). Having identified the essential role of LPI in PDAC progression and the transporter responsible for its secretion, we now have the opportunity to target the transporter and reduce the level of LPI in the tumour environment and interfere with cancer progression.
    Initial indications that ABCC3 is a viable therapeutic target in PDAC was evident from genetic knockdown experiments which reduced PDAC anchorage-dependent and independent cell growth. Moreover, we showed that ABCC3 regulates STAT3 and HIF1α signalling pathways, key regulators of PDAC development and progression. It has been reported that constitutive activation of STAT3 signalling negatively affects the survival of PDAC patients (Wormann et al., 2016). It is known that STAT3 signalling is triggered by IL6 activation of gp130 (Corcoran et al., 2011; Lesina et al., 2011). However, a recent study suggested the existence of gp130-independent STAT3 activation in PDAC (Wormann et al., 2016), which is consistent with our findings of ABCC3-mediated STAT3 induction. These results suggest that ABCC3-regulated function of STAT3 and HIF1α may represent the potential mechanism of ABCC3- mediated PDAC progression.
    Apart from the high chemoresistance of PDAC tumours, the unsuccessful outcome of the majority of clinical trials in PDAC can also be attributed to the lack of proper stratification of patients into cohorts and to the failure to target therapies based on the mutational landscape. We show herein that the expression of ABCC3 is dependent on the genetic status of TP53, one of the main genes dysregulated in PDAC. Wild type p53 levels negatively correlate with ABCC3 mRNA and protein levels and this relationship appears to be mediated by miR-34C whose expression is dependent on p53 activity and is therefore usually downregulated in pancreatic cancer (He et al., 2007; Ji et al., 2009) (Fig. 6). It has been previously documented that in PDAC, constitutive activation of both HIF1α and STAT3 pathways is dependent on the TP53 mutation or deletion (Wormann et al., 2016), which is consistent with our findings. It has also been shown that one of the mechanisms regulating the expression of the miR34 family involves pSTAT3, whose increased expression in TP53 mutated samples blocks the activity of miR34a (Slabáková et al., 2017). Similarly, in colorectal cancer, HIF1α activity in hypoxic conditions also represses Pyocyanin miR34a expression and affects STAT3 signalling (Li et al., 2017). It is tempting to speculate whether the activity of miR34-C might also be affected by STAT3 and HIF1α signalling in pancreatic cancer. Therefore, STAT3 and HIF1α downregulation through ABCC3 blockade might eliminate their inhibitory effect on miR34-C activity, which in turn would lower ABCC3 expression. This feed-forward loop might provide the mechanism by which pharmacological targeting of ABCC3 could reprogram pancreatic cancer cells and potentially slow down the disease progression and increase patient survival.