探討胰臟癌誘導糖尿病中 HIF-1α介導的S100A9表現機轉以及功能

Abstract

胰臟癌是一種高度致死率的腫瘤，其臨床特徵包括進展迅速、診斷困難以及預後不良。由於約 80-90% 的患者在疾病晚期才被確診，錯失手術治療的時機，導致五年內生存率普遍低於 10%。研究顯示，約有半數胰臟癌患者在確診前一年內出現新生糖尿病，而此類患者於後續一至三年間罹患胰臟癌的風險顯著升高，顯示與胰臟惡性腫瘤相關的新生糖尿病 (PCDM) 可能為胰臟癌的潛在早期徵兆。本實驗室先前研究發現， PCDM 患者的腫瘤組織中，具有高度表現的 S100A9，此分子會導致骨骼肌產生胰島素阻抗，並降低胰島 β 細胞的胰島素生成能力。然而， S100A9 在胰臟癌細胞中表現上升的機制，及其對胰臟癌惡性行為的影響仍有待釐清。 本研究建立了 S100A9 過表現之胰臟癌細胞株 MIA PaCa-2，結果顯示 S100A9 可促進癌細胞之增生、遷移與侵襲能力;此外，我們發現 S100A9 表現會在缺氧環境中進一步上升。 Tasquinimod 作為一種 HDAC4 抑制劑，在缺氧條件下能減少 HDAC4、 HDAC3 與 HIF-1α 之間的交互作用，同時抑制 HIF-1α 表現，進而降低 S100A9 蛋白表現。進一步在臨床檢體中驗證， PCDM 患者腫瘤組織中的 S100A9 與 HIF-1α 表現皆明顯高於非糖尿病胰臟癌 (PC) 患者。 綜合上述結果， S100A9 在胰臟癌增生與轉移，以及在 PCDM 形成中具有關鍵調控角色，極具潛力作為胰臟癌早期生物標誌; Tasquinimod 具備同時抑制胰臟癌進展及緩解糖尿病相關症狀的潛力，未來可望作為治療 PCDM 的創新治療策略。

Pancreatic cancer is a highly lethal malignancy, characterized by its insidious onset and the limited sensitivity of current diagnostic tools. As a result, approximately 80–90% of patients are diagnosed at an advanced stage, making them ineligible for surgical resection and contributing to a poor overall long-term survival rate of only 1–5%. Previous studies have shown that around 50% of pancreatic cancer patients develop new- onset diabetes approximately one year before diagnosis. Moreover, individuals with new- onset diabetes have a 5- to 8-fold increased risk of being diagnosed with pancreatic cancer within the subsequent 1 to 3 years. These findings suggest that pancreatic cancer-induced diabetes (PCDM) may serve as a potential early indicator of the disease. Our previous study demonstrated that tumor tissues from PCDM exhibit markedly elevated levels of S100A9, a diabetogenic factor that induces insulin resistance in skeletal muscle and impairing insulin production in pancreatic β cells. However, the molecular mechanisms driving S100A9 upregulation in pancreatic cancer cells and its role in tumor progression remain unclear. In this study, we established a S100A9-overexpressing pancreatic cancer cell line (MIA PaCa-2) and found that S100A9 promotes cancer cell proliferation, migration, and invasion. Furthermore, S100A9 expression was found to be further increased under hypoxic conditions. Tasquinimod, an HDAC4 inhibitor, was shown to disrupt the interaction among HDAC4, HDAC3, and HIF-1α under hypoxia, thereby downregulating both HIF-1α and S100A9 expression. Immunohistochemical staining of clinical specimens confirmed that S100A9 and HIF-1α levels were significantly elevated in tumor tissues from PCDM patients compared to those from non-diabetic pancreatic cancer (PC) patients. Taken together, these findings demonstrate that S100A9 plays a pivotal role in promoting pancreatic cancer cell proliferation and metastasis, and the pathogenesis of PCDM. S100A9 may serve as a promising early biomarker for pancreatic cancer. In addition, Tasquinimod shows potential as a novel therapeutic strategy capable of both inhibiting pancreatic cancer progression and alleviating diabetes-associated symptoms in PCDM patients.