GALNT2調控大腸直腸癌細胞轉移之角色

Abstract

大腸直腸癌是世界上第三大最常被診斷的惡性腫瘤，也是癌症死亡的第二大原因。它的發展歷時數年，從良性腺瘤性瘜肉開始變成具有高度異型增生的腺瘤，然後發展為侵襲性癌症。轉移性大腸癌的預後很差，5年存活率不到20%，有腹膜轉移的患者的整體存活率比癌細胞轉移到肝臟或肺臟的患者要差。因此，開發更敏感的診斷標誌物和轉移性大腸癌的新治療方法迫在眉睫。 蛋白質轉譯後修飾最常見的是醣化，異常醣化經常在許多癌症中觀察到，但其在腫瘤發生所扮演之角色尚須進一步釐清。醣化有兩種主要的類型分別是氮型和氧型，在氧型醣化中，N-乙醯基半乳糖胺通過GalNAc轉移酶 (GALNT) 連接到位於高基氏體中的絲氨酸或蘇氨酸上。 在20種GALNT同功酶中，根據資料庫顯示GALNT2與大腸癌患者的不良存活率相關。我們的研究指出，與鄰近的非腫瘤組織相比，GALNT2在大腸癌組織中是過度表現且與患者的低存活率相關。GALNT2的過度表現促進大腸癌細胞的遷移和侵襲，相反，抑制GALNT2的表現則會顯著降低癌細胞侵襲性；在腹腔注射模擬癌細胞轉移的活體小鼠 (NOD/SCID mice) 模型實驗中也是跟癌細胞有相同實驗結果。有趣的是，我們發現GALNT2會修飾受體酪氨酸激酶AXL上的氧型聚醣，並通過蛋白酶體途徑調控AXL表現量。此外，AXL抑製劑和小分子核醣核酸顯著逆轉GALNT2促進的侵襲性。這些發現證明GALNT2會部分影響AXL上氧型聚醣進而促進大腸癌侵襲。

Colorectal cancer (CRC) is the third most commonly diagnosed malignancy and the second leading cause of cancer death in the world. Colorectal neoplasms take years to develop, initially as benign adenomatous polyps, as advanced adenomas with high-grade dysplasia, and then as invasive tumors. The prognosis of metastatic CRC is poor, with a 5-year survival rate of less than 20%. CRC patients with peritoneal metastasis have poorer overall survival than those with liver or lung metastasis. Therefore, it is urgent to develop more sensitive diagnostic markers and new treatment of metastatic colorectal cancer. The most common and complex post-translational modification of proteins is glycosylation. Abnormal glycosylation is frequently observed in many types of cancer, but it is unclear if it contributes intrinsically to tumorigenesis. There are two major types of glycosylation: N-linked and O-linked. In O-glycosylation, an N-Acetylgalactosamine (GalNAc) is attached to Ser (S) or Thr (T) residues in the Golgi by GalNAc-transferases (GALNTs). Among 20 GALNT isoenzymes, GALNT2 is consistently associated with poor survival of patients with colorectal cancer in public databases. In our study, immunohistochemistry revealed that GALNT2 was overexpressed in colorectal cancer tissues compared with adjacent non-tumor tissues. GALNT2 overexpression was significantly associated with poor survival of patients with colorectal cancer. In vitro and animal experiments showed that reducing the expression of GALNT2 inhibited the migration, invasion and peritoneal metastasis of colon cancer cells. Interestingly, we found that O-glycans on AXL were modified by GALNT2 and determined AXL levels through a proteasome-dependent pathway. Additionally, both the AXL inhibitor and siRNA significantly reversed the GALNT2-mediated invasiveness. In conclusion, we demonstrate that GALNT2 promotes colorectal cancer invasion at least in part through AXL.