Abstract
BackgroundCholangiocarcinoma is a highly malignant cancer with very dismal prognosis. Perihilar cholangiocarcinoma(pCCA) accounts for more than 50% of all cholangiocarcinoma and is well-characterized for its low rate of radical resection. Effects of radiotherapy and chemotherapy of pCCA are very limited.MethodsHere we screened potential biomarkers of pCCA with transcriptome sequencing and evaluated the prognostic significance of HMGA1 in a large cohort pCCA consisting of 106 patients. With bioinformatics and in vitro/vivo experiments, we showed that HMGA1 induced tumor cell stemness and epithelial-mesenchymal-transition (EMT), and thus facilitated proliferation, migration and invasion by promoting TRIP13 transcription. Moreover, TRIP13 was also an unfavorable prognostic biomarker of pCCA, and double high expression of HMGA1/TRIP13 could predict prognosis more sensitively. TRIP13 promoted pCCA progression by suppressing FBXW7 transcription and stabilizing c-Myc. c-Myc in turn induced the transcription and expression of both HMGA1 and TRIP13, indicating that HMGA-TRIP13 axis facilitated pCCA stemness and EMT in a positive feedback pathway.ConclusionsHMGA1 and TRIP13 were unfavorable prognostic biomarkers of pCCA. HMGA1 enhanced pCCA proliferation, migration, invasion, stemness and EMT, by inducing TRIP13 expression, suppressing FBXW7 expression and stabilizing c-Myc. Moreover, c-Myc can induce the transcription of HMGA1 and TRIP13, suggesting that HMGA-TRIP13 axis promoted EMT and stemness in a positive feedback pathway dependent on c-Myc.
Highlights
Cholangiocarcinoma is a highly malignant cancer with very dismal prognosis
Among the HMG family, only High mobility group A1 (HMGA1) was significantly upregulated in Perihilar cholangiocarcinoma (pCCA) compared with adjacent bile duct tissues (Fig. 1a)
In a retrospective cohort of patients with pCCA radical resection (n = 106), the expression and localization of HMGA1 were detected with IHC
Summary
Perihilar cholangiocarcinoma(pCCA) accounts for more than 50% of all cholangiocarcinoma and is well-characterized for its low rate of radical resection. The effects of radiotherapy and chemotherapy of pCCA are very limited, and studies on pCCA are far behind those of other more common tumors such as lung cancer and colon cancer in this era of precision treatment [7]. Several reasons can be attributed to, including (i) the prevalence of pCCA is relatively low, making a large cohort difficult to establish; (ii) pCCA specimens are hard to obtain because of its special anatomical location, resulting in rare reports on pCCA high-throughput experiments; (iii) most patients lose surgical opportunity and the survival times are so short to perform any experimental treatment. Further studies of the pathogenesis and therapeutic options of pCCA are necessary
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