Abstract
Background:LIN28B is functionally driving malignant transformation and relevance to the worse disease outcomes by promoting cancer aggressiveness. However, a typical role of LIN28B in cholangiocarcinoma (CCA) is primarily unknown. In this study, the tumorigenic potential of LIN28B in the cholangiocyte context was investigated. Methods: Stable LIN28B expression in MMNK-1 cells was generated by infecting with retrovirus-containing LIN28B gene. LIN28B-overexpressing cells were further validated the amount of released cytokines by using human cytokine arrays. After treatment of chemo-drugs, cell viability was subsequently measured using MTT assay. Aldehyde dehydrogenase (ALDH) activity was determined using ALDEFLUOR assay Kit and analyzed by flow cytometry. The mRNA and protein expression levels were respectively assayed by RT-qPCR and western blot. Results:Cytokine release results showed that numerous inflammatory cytokines-chemokines related to cancer initiation and development, such as IL-8, IL-6, VEGF, MCP1, TNF-α were significantly increased in LIN28B-overexpressing MMNK-1 cells. Drug sensitivity test showed that LIN28B-overexpressing MMNK-1 treated cells had a high percentage of cell viability compared to MMNK-1-control treated cells. Activity and expression level of a cancer stem cell marker, ALDH was significantly elevated in LIN28B-overexpressing MMNK-1 cells. Moreover, the activation of an oncogenic signaling pathway, signal transducer and activator of transcription 3 (STAT3) was enhanced in LIN28B-overexpressing MMNK-1 cells. Whereas, growth capacity of LIN28B-overexpressing MMNK-1 cells was found to be reduced in STAT3 inhibition. Conclusion:LIN28B can regulate the inflammatory response and resistance to chemotherapy of cholangiocytes through modulation of STAT3 signaling pathway.A recent study suggests that activated cholangiocytes can be induced by regulation of LIN28B/STAT3 pathway and this may partially contribute to the initiating CCA. Here, LIN28B and its downstream signaling could be considered as an attractive therapeutic target in patients with CCA.
Highlights
Cholangiocarcinoma (CCA) is recognized as a devastating cancer with limited therapeutic options and poor prognosis
As revealed by cytokine array, we found that the amount of release inflammatory cytokines such as IL-8, IL-6, MCP-1, VEGF, IFN-γ and Tumor necrosis factor-α (TNF-α) were significantly increased in LIN28Boverexpressing MMNK-1 cells (Figure 1)
In the different contexts of LIN28B-expressing cells, we found that the expression levels of IL-6 and IL-8 genes were increased in LIN28B-overexpressing HuCCT1 cells (Supplementary Figure 2a-b)
Summary
Cholangiocarcinoma (CCA) is recognized as a devastating cancer with limited therapeutic options and poor prognosis. Impaired inflammation is well known as an impact factor that plays a critical role in cholangiocarcinogenesis by causing genetic aberrationand activating several oncogenic signaling pathways (Andersen and Thorgeirsson, 2014). According to such knowledge, several potential therapeutic targets for CCA were suggested.the dominating molecular signaling which plays an especially early role in the transformation process is largely unclear. Results: Cytokine release results showed that numerous inflammatory cytokines-chemokines related to cancer initiation and development, such as IL-8, IL-6, VEGF, MCP1, TNF-α were significantly increased in LIN28B-overexpressing MMNK-1 cells. Activity and expression level of a cancer stem cell marker, ALDH was significantly elevated in LIN28B-overexpressing MMNK-1 cells. LIN28B and its downstream signaling could be considered as an attractive therapeutic target in patients with CCA
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