HOTTIP Enhances Gemcitabine and Cisplatin Resistance Through Sponging miR-637 in Cholangiocarcinoma

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.

Long Non-Coding RNAs as Molecular Biomarkers in Cholangiocarcinoma

“…Most of the lncRNA-related research has focused on the mechanism and function of dysregulated lncRNAs in the tissues and cells of CCA. The following lncRNAs have been documented to be linked to the prognosis of cholangiocarcinoma ( Table 2 ): ANRIL ( Angenard et al, 2019 ), ASAP1-IT1 ( Guo et al, 2018 ), CCAT1 ( Zhang et al, 2017a ), CCAT2 ( Xu et al, 2018a ), CRNDE ( Xia et al, 2018 ), FOXD2-AS1 ( Hu et al, 2022 ), GAPLINC ( Wang et al, 2018 ), H19 ( Xu et al, 2017a ), HOTAIR ( Qin et al, 2018 ), HOTTIP ( Gao et al, 2021 ), HOXD-AS1 ( Li et al, 2020b ), LINC00261 ( Gao et al, 2020 ), LINC00665 ( Lu et al, 2021 ), LINC00667 ( Li et al, 2021a ), LINC01296 ( Zhang et al, 2018a ), LOXL1-AS1 ( Zhang et al, 2019a ), NNT-AS1 ( Huang et al, 2019a ), MALAT1 ( Tan et al, 2017 ), PAICC ( Xia et al, 2020 ), PANDAR ( Xu et al, 2017b ), PCAT1 ( Sun et al, 2021 ), lnc-PKD2-2-3 ( Qiu et al, 2019 ), SNHG3 ( Tian et al, 2019 ), Sox2ot ( Li et al, 2018 ), TUG1 ( Xu et al, 2017c ), UCA1 ( Xu et al, 2017d ), ZEB1-AS1 ( Jiang et al, 2020a ), ZFAS1 ( Li et al, 2019c ).…”

“…Recently, studies have identified lncRNAs as important players in CCA chemoresistance. So far, a few novel lncRNAs, including NEAT-1, LINC01714, HOXD-AS1, HOTTIP, LINC00665, and lnc-PKD2-2-3, have been revealed to modulate chemoresistance in CCA ( Figure 2 ) ( Lu et al, 2021 ; Qiu et al, 2019 ; Li et al, 2020b ; Gao et al, 2021 ; Parasramka et al, 2017 ; Shen et al, 2020 ). These resistance-associated lncRNAs present new opportunities for the treatment of CCA.…”

“…Additionally, overexpressed LINC01714 facilitated the susceptibility of CCA cells to gemcitabine by reducing phosphorylated FOXO3-Ser318 ( Figure 1B ), which indicated that LINC01714 transcription promoter and gemcitabine combined with chemotherapy may have a synergistic effect on the treatment of advanced CCA patients ( Shen et al, 2020 ). LncRNA HOTTIP and HOXD-AS1 were reported to regulate the sensitivity of CCA cells to gemcitabine and cisplatin through sponging miR-637 to increase LASP1 and sponging miR-520c-3p to increase MYCN, respectively ( Figures 2C,D ) ( Li et al, 2020b ; Gao et al, 2021 ). The acquisition of EMT and the existence of CSC are not only crucial mechanisms in the invasion and metastasis of CCA, but recent investigations have established that they may be closely linked to the chemoresistance of CCA ( Huang et al, 2019c ; Varamo et al, 2019 ).…”

Lnc-PKD2-2-3/miR-328/GPAM ceRNA Network Induces Cholangiocarcinoma Proliferation, Invasion and 5-FU Chemoresistance

“…Long non-coding RNA (lncRNA), as a newly discovered type of RNA in the current century with a length of more than 200 bp but less protein-coding ability, has been discovered to be closely involved in the pathogenesis of various cancers (11)(12)(13)(14). In the aspect of CCA, several specific lncRNAs have been discovered to participate in CCA initiation or progression (15)(16)(17)(18). For instance, lncRNA SNHG3 promotes CCA cell proliferation and migration via mediating the miR-3173-5p/ERG axis (15); lncRNA FAM66C induces CCA growth, mobility, and glycolysis by modifying miR-23b-3p/KCND2 in vitro and in vivo (16); and lncRNA HOTTIP elevates drug resistance of gemcitabine and cisplatin via sponging miR-637 in CCA (18).…”

“…In the aspect of CCA, several specific lncRNAs have been discovered to participate in CCA initiation or progression (15)(16)(17)(18). For instance, lncRNA SNHG3 promotes CCA cell proliferation and migration via mediating the miR-3173-5p/ERG axis (15); lncRNA FAM66C induces CCA growth, mobility, and glycolysis by modifying miR-23b-3p/KCND2 in vitro and in vivo (16); and lncRNA HOTTIP elevates drug resistance of gemcitabine and cisplatin via sponging miR-637 in CCA (18). However, the engagement of a great number of lncRNAs in CCA is not dragged out, and comprehensive exploration is lacking.…”