Abstract
Chemo-resistance prominently hampers the effects of systemic chemotherapy to cholangiocarcinoma (CCA). Long non-coding RNAs (lncRNAs) have been shown to have great importance not only in tumorigenesis but also in therapeutic prognosis. The aim of this study is to investigate the role of lncRNA HOTTIP in the chemo-resistance to cisplatin and gemcitabine (CG) in CCA. The upregulated expression of HOTTIP was observed in CCA patients and the upregulation was associated with therapeutic responsiveness and prognosis. HOTTIP silencing powerfully increased the chemotherapy sensitivity through weakening proliferation and colony formation and increasing apoptosis. Subsequently, miR-637 was identified as the functional target of HOTTIP, since mechanically it could be targeted by HOTTIP and functionally its overexpression dismissed the changes by HOTTIP silencing in vitro and in vivo. Moreover, LIM and SH3 domain protein 1 (LASP1) could be targeted and regulated by miR-637. In all, HOTTIP modulates the sensitivity to CG in CCA through the HOTTIP/miR-637/LASP1 regulatory axis, providing a new opportunities for CCA treatment.
Highlights
Cholangiocarcinoma (CCA) is one kind of primary liver cancer originating from bile duct epithelial cells
The results showed that LIM and SH3 domain protein 1 (LASP1) expression level decreased with siHOTTIP transfected into the CCLP-1 cells and the decreased LASP1 expression was reversed with miR-637 inhibition (Figure 5D)
Since the majority of CCA patients are unsuitable for surgery, chemotherapy remains the principal treatment for CCA
Summary
Cholangiocarcinoma (CCA) is one kind of primary liver cancer originating from bile duct epithelial cells. It ranks after hepatocellular carcinoma in morbidity accounting for an approximate 15% of primary liver cancers. CCA patients suffer very poor prognosis due to high malignancy [1]. The majority of patients have lost their opportunity for radical surgery since they are diagnosed in the advanced stage. The standard systemic chemotherapy employing gemcitabine and cisplatin can only provide a modest therapeutic effect [2]. It is urgently needed to expand the knowledge of the mechanisms modulating the chemotherapy responsiveness in cholangiocarcinoma [3]
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