胰腺癌是世界上最致命的惡性腫瘤之一，其五年存活率僅有9％。在導管上皮細胞中細胞極性具有維持胰腺的組織結構的功能，然而細胞極性通常在分化不良的癌化上皮細胞中會被消除。NOP2/Sun RNA methyltransferase 2（NSUN2）為一種甲基轉移酶，能在RNA的胞嘧啶上進行甲基化修飾，並發現其在一些癌細胞中會上調，以促進細胞增生和侵襲。由於NSUN2在胰腺癌中的作用機制尚不清楚，了解其調節胰腺腫瘤中細胞分化的機制是很重要。在本研究中，我們假設NSUN2可能調節胰腺癌進程中的細胞極性和上皮分化。首先，我們通過qPCR確定NSUN2是否可以調節細胞極性基因的表現。此外，我們通過免疫組織化學染色測定胰腺癌切片中NSUN2和CK19的蛋白表達量，檢體包括胰腺癌病程前期KrasG12D / +;Pdx1-Cre（KC）小鼠以及早期和晚期的KrasG12D / +，Trp53fl / fl;Pdx1-Cre（KPC）小鼠。我們的數據顯示，NSUN2在晚期KPC小鼠胰腺上皮內癌變（PanIN）的表達量上升。最後，為了確認NSUN2表達是否可能促進體內腫瘤進程，我們使用控制組和NSUN2敲低的胰臟癌細胞進行皮下注射以比較兩者腫瘤生長的差異。皮下注射的腫瘤切片在敲低NSUN2基因組中顯示出分化較良好的組織結構。總結而論，我們的結果表示NSUN2可能在胰腺癌發展過程中扮演失調上皮分化的角色。

Pancreatic cancer is one of the deadliest malignant tumors worldwide with a five-year survival rate of only 9%. Cellular polarity of ductal epithelial cells, which functions to maintain the tissue architecture of the pancreas, is often abolished in poorly-differentiated cancer cells. NOP2/Sun RNA methyltransferase 2 (NSUN2) catalyzes the deposition of methyl moiety onto cytosines in RNA and it is upregulated in several cancer types to promote cell proliferation and invasion. The role of NSUN2 in pancreatic cancer remains unclear, it is important to understand its mechanism that regulates cellular differentiation in pancreatic tumorigenesis. Firstly, we determined the protein expression level of NSUN2 and CK19 by immunohistochemistry in a set of pancreatic sections, including those of precancerous KrasG12D/+;Pdx1-Cre (KC) mice and the early and the late stages of KrasG12D/+;Trp53fl/fl;Pdx1-Cre (KPC) mice. Our data showed an increase NSUN2 expression in pancreatic intraepithelial neoplasia (PanIN) and PDAC in late-stage KPC mice. Further, we determined NSUN2 could regulate the expression of cellular polarity genes by qPCR and western blot. Finally, to examine whether NSUN2 expression promotes tumor progression in vivo, subcutaneous implantation model using the control and the NSUN2 knockdown cancer cells were conducted for comparing differences of tumor growth. Tumoral sections of the resulting grafts showed properly differentiated tissue structure in the NSUN2 knockdown group. In summary, our data support that NSUN2 plays a role in the dysregulation of epithelial differentiation during pancreatic cancer development.

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