胰導管腺癌目前仍是最惡性的癌症之一，其五年內存活率僅不到5%。大部分病人在初次被診斷出患有胰導管腺癌時，已伴隨著癌細胞的擴散，可能是造成如此低存活率之原因。淋巴管是最常見的實質腫瘤轉移路徑，因此，淋巴管新生促進因子表達的增加，在胰導管腺癌中可能扮演著重要的角色。我們先前研究發現一個重要的抑癌基因，雙特異性去磷酸酶-2，其表達在許多癌症中都大幅地降低甚至不表現，而此低表現導致許多癌症惡性徵狀。因此，我們亟欲探討雙特異性去磷酸酶-2表達下降在高度轉移性的胰導管腺癌中引起之病理後果並瞭解其下游調控機制。利用基因微陣列分析，發現一主要淋巴管新生促進因子，血管內皮生長因子-C，其表達可能受雙特異性去磷酸酶-2負調控。我們假設雙特異性去磷酸酶-2表達下降導致血管內皮生長因子-C之表現提升，進而促進胰導管腺癌細胞爬行與癌症轉移能力。利用表達載體轉染胰導管腺癌細胞株我們證實了雙特異性去磷酸酶-2對於血管內皮生長因子-C之負調控。作為生長因子，血管內皮生長因子-C必須分泌至細胞外並修飾成為有功能之蛋白質。我們發現雙特異性去磷酸酶-2不僅促進血管內皮生長因子-C之轉錄，並對其獲取功能的後轉譯修飾有所影響。為探討雙特異性去磷酸酶-2負調控之血管內皮生長因子-C功能，我們利用富含血管內皮生長因子-C的雙特異性去磷酸酶-2抑制表達胰導管腺癌細胞之培養基，探討其中之血管內皮生長因子-C是否能促進淋巴新生，結果顯示其培養基確實促進淋巴內皮細胞之生長與爬行。在免疫缺陷小鼠之異種移植腫瘤細胞模式中，進一步證明抑制雙特異性去磷酸酶-2之胰導管腺癌細胞所形成之腫瘤有較高程度的淋巴管新生。血管內皮生長因子-C除了對淋巴管新生之旁分泌功能外，也能透過自體分泌而促進胰導管腺癌細胞之侵略性。抑制雙特異性去磷酸酶-2之胰導管腺癌細胞表現了較高的穿透移行侵襲能力，此現象在抑制血管內皮生長因子-C訊息路徑後隨之降低。抑制血管內皮生長因子-C之胰導管腺癌細胞也顯示較低之移行能力。我們的研究指出，在胰導管腺癌之進程中，雙特異性去磷酸酶-2之表現降低導致血管內皮生長因子-C的高度表達，此功能性血管內皮生長因子-C能夠利用旁分泌促進淋巴管新生，並且經由自體分泌使癌細胞更具侵略性而促使胰導管腺癌惡化。我們相信，以血管內皮生長因子-C作為標的或同時重建雙特異性去磷酸酶-2之表現，將可能作為一個具有潛力的治療方針，以抑制胰導管腺癌之進展。另外，抑制血管內皮生長因子-C被轉譯後修飾成功能性蛋白質之酵素路徑，可能為另一種有前景的方式來抑制胰導管腺癌之擴散與惡化。

Pancreatic ductal adenocarcinoma (PDAC) remains as one of the most malignant cancers with less than 5% 5-year survival rate. The low survival rate is due, at least in part, to late diagnosis since most PDAC patients were first diagnosed after the tumor has disseminated. Lymphatic vessels are the most common route for solid tumor cells to spread, therefore, the increased expression of lymphangiogenic growth factors may play a critical role in PDAC metastasis. Our previous study found dual specificity phosphatase 2 (DUSP2), a critical tumor suppressor gene in controlling multiple cancer malignancy, is markedly decreased in many cancers. We herein further investigate the pathological consequence of DUSP2 downregulation in PDAC metastasis. To dissect the underlying mechanism, we performed microarray analysis and the data indicated one critical lymphangiogenic factor, vascular endothelial growth factor C (VEGF-C), is negatively regulated by DUSP2. We hypothesized that downregulation of DUSP2 in PDAC cells promotes tumor cell migration and metastasis by up‐regulation of VEGF‐C. Knockdown of DUSP2 increased VEGF-C expression while overexpression of DUSP2 decreased VEGF-C in PDAC cells. As a growth factor, VEGF-C has to be cleaved and secreted to extracellular space to be functional. We demonstrated that loss-of-DUSP2 not only stimulates VEGF-C transcription but also regulates VEGF-C cleavage at the post-translational level as evidenced by that loss-of-DUSP2-enhanced VEGF-C secretion was diminished by addition of proprotein convertase inhibitor. To test whether loss-of-DUSP-induced VEGF-C promotes lymphangiogenesis, conditioned media from DUSP2 knockdown cells were used to treat lymphatic endothelial cells (LECs). As expected, the conditioned media with elevated expression of VEGF-C promoted migration and growth of LECs, and in vivo animal study also demonstrated that DUSP2 knockdown tumors developed more lymphatic vessels, strongly suggesting that inhibition of DUSP2 promotes lymphangiogenesis via up-regulation of VEGF-C. In addition to the paracrine effect on LECs, we found that VEGF-C promotes cancer cells migration via an autocrine mechanism. Knockdown of VEGF-C in PDAC cells significantly decreased cell invasion whilst enhanced invasion ability by DUSP2 knockdown can be abolished by treatment with VEGFR2/VEGFR3 inhibitor, lenvatinib. Thus, loss-of-DUSP2-mediated VEGF-C upregulation can induce lymphatic vessel infiltration to the cancer tissue and, at the same time, increase pancreatic cancer cell migration to promote cancer cell dissemination. Taken all together, our results indicate that downregulation of DUSP2 during pancreatic cancer progression may lead to increased VEGF-C expression, which promotes cancer malignancy via paracrine (lymphangiogenesis) and autocrine (tumor cell migration) mechanisms. Our findings suggest that targeting VEGF-C or restoration of DUSP2 simultaneously may serve as an attractive therapeutic approach to inhibit pancreatic cancer progression. Alternatively, inhibiting VEGF-C from being processed by convertase might be another promising approach to inhibit PDAC dissemination and cancer malignancy.

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