胰管腺癌(PDAC)被視為高度惡性的癌症，其五年存活率相較於各癌症亦是最低的。直至現在，胰管腺癌仍亟需找出早期診斷標的物及發展有效的抗癌藥物。由於胰管腺癌被認為是一種代謝失衡的疾病，針對其代謝依賴性的特點可能發展出具潛力的抗癌新策略。
SIK3隸屬於AMPK家族中的SIK次家族，過去我們實驗室發現SIK3做為卵巢癌的腫瘤相關抗原，能夠藉由活化c-Src-PI3K的機制來促進細胞週期G1/S進程，因而參與了卵巢癌的腫瘤生成。除此之外，近年的研究也發現SIK3能在小鼠肝細胞中調控葡萄糖的代謝。值得一提的是，動物實驗觀察到SIK3剔除小鼠表現出葡萄糖代謝異常而導致的酮尿，而該基因剔除小鼠可能由於脂肪組織的缺失而表現出瘦表型(lean phenotype)，這與體重普遍減輕的具有第二型糖尿病的胰管腺癌患者通常具有廣泛的骨骼肌和脂肪組織損失這項特徵類似。因此，我們對於SIK3是否在胰管腺癌的代謝中扮演著什麼角色感到有興趣。
於此篇研究中我們首先利用免疫組織染色切片觀察到胰管腺癌的患者以及自發性生成胰臟癌的基因改造小鼠(利用Cre重組酶在胰臟組織中專一表現具有Kras第12密碼子點突變、KLF10以及p53剔除的轉殖小鼠，簡稱KKPC)的組織切片其SIK3表現較低。而透過TCGA資料庫中的胰管腺癌患者資料進行存活率分析，由存活曲線圖亦可以觀察到SIK3表現量被定義為低的患者，具有較差的預後。在細胞實驗，利用外送與SIK3序列互補的shRNA以及處理 pan-SIK抑制劑HG9-91-01，我們發現去除SIK3會在MIA PaCa-2與PANC-1胰管腺癌細胞中導致HDAC5的去磷酸化、及增加了糖質新生起始步驟之酵素-磷酸烯醇丙酮酸羧化激酶Pck1與葡萄糖載體蛋白Glut2的基因轉錄，但不影響CRTC2、CREB的活性。此機制最終增加了胰管腺癌細胞的反應糖解作用活性(extracellular acidification rate, ECAR)及瓦氏效應(Warburg effect)。而此種代謝異常現象在經過降低HDAC5表達後可被逆轉，代表HDAC5確實做為SIK3下游調控能量代謝的調節者。未來將可探討抑制HDAC5在KKPC小鼠中是否有做為治療手段的潛力。整體而言，在此篇研究中我們發現SIK3在PDAC中扮演透過調節葡萄糖代謝來控制細胞能量代謝的關鍵調控者。

Pancreatic duct adenocarcinoma (PDAC) is known as a highly-malignant cancer, and the patients have the lowest five-year survival rate among a variety of cancers. Obviously, discovery of early diagnostic markers and development of effective anticancer drugs are urgently needed. Since PDAC has been considered as a metabolic cancer type, many lines of evidence suggest that targeting its metabolic dependency may be a potential strategy for cancer treatment in future.
Salt-inducible kinase (SIK) subfamily belongs to the AMPK-related kinases (AMPK-RK). In this subfamily, there are three members identified, SIK1, SIK2, and SIK3. SIK3 was identified as a tumor-associated antigen by our lab, which is involved in ovarian tumorigenesis by promoting cell-cycle G1/S transition through activation of c-Src-PI3K signaling linkage. In addition, SIK3 was recently reported to play a pivotal role in the glucose metabolism of hepatocytes. Meanwhile, in vivo study demonstrated that mice with SIK3 loss developed ketonuria (glucose metabolic disorder) and displayed a lean phenotype attributed to the loss of adipose tissues. These features resemble to most of PDAC patients who have type II diabetes and suffer weight loss, characterized by the loss of extensive skeletal muscle and adipose tissues. Thus, we are interested in whether SIK3 plays a role in PDAC.
In the present study, immunohistochemical analysis of SIK3 expression in patients with PDAC and in mice with KLF10L/L/KrasG12D/p53L/L/pdx1-Cre (KKPC), a spontaneous PDAC mouse model, showed that SIK3 expression was significantly downregulated. The Kaplan–Meier analysis using the PDAC patient information from the TCGA database also demonstrated that lower expression of SIK3 was significantly correlated with a poorer prognosis in 5-year survival (P<0.05). Experiments using the SIK3-specific small hairpin interfering RNA (shRNA) technique and HG9-91-01 (pan-SIK inhibitor) demonstrated that attenuation of SIK3 could cause dephosphorylation of HDAC5, increase transcriptional activation of gluconeogenic gene Pck1 as well as glucose transporter gene Glut2, but not affect the activation of CRTC2, CREB in MIA PaCa-2 and PANC-1 PDAC cells. The signaling outcomes led to a marked increase in extracellular acidification rate (ECAR) and glycolytic activity (Warburg effect) in PDAC cells. However, these phenomena were reprogrammed by knockdown of HDAC5 expression, showing a consequent alteration in expression of its downstream gluconeogenic genes Pck1 and G6pc (encode PEPCK and G6Pase, respectively) as well as in the glucose transporter gene Glut2 of PDAC cells. In future, the therapeutic effect of HDAC5 inhibition will be closely examined in the KKPC mouse model. Collectively, SIK3 is a key regulator to control the balance of cellular energy metabolism by modulation of glucose utilization in PDAC.

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