胰臟癌仍然是預後最差的癌症之一，全世界5年存活率約5-6%。其預後差的原因主要為晚期診斷、容易早期擴散及轉移，及對化療藥物的抗藥性。了解胰臟癌的進展機制或許能提供新的治療方式。胰臟癌源自於胰臟管腔且常會阻塞胰管，因此胰管充滿胰液及胰臟癌相關蛋白。利用蛋白質體分析胰液蛋白質術前術後的變化，發現TBC1D23在手術後的濃度有明顯下降。TBC1D23是一個GTPase的活化蛋白，主要參與內質體至高基氏體的訊息傳送。臨床上在胰臟癌的組織染色發現，癌細胞有TBC1D23高表現的病人預後較差且有較高的機率發生淋巴轉移。同時在血清中也發現胰臟癌的病人TBC1D23的濃度相較於正常人來的高。
在細胞功能研究方面，我們發現TBC1D23在大部份的胰臟癌細胞株相較於正常胰臟細胞有較高的表現。之後我們建立阻斷TBC1D23表現的胰臟癌細胞株(PANC-1及BxPC-3)，發現TBC1D23阻斷後會抑制腫瘤細胞的生長及位移。在老鼠實驗，將阻斷的TBC1D23移入老鼠胰臟後會抑制腫瘤生長及淋巴轉移的情形。在利用Microarray的分析發現VEGF-C這個基因在阻斷TBC1D23後也被抑制了，同時VEGF-C mRNA表現、VEGF-C蛋白質分泌也減少了。在淋巴管生成的實驗發現，TBC1D23的細胞株能增進淋巴細胞淋巴管的形成但阻斷TBC1D23表現後淋巴管的形成就被抑制。
VEGF-C表現的其中一個路徑是經由EGFR所控制同時EGFR也是胰臟癌生成的重要基因。在免疫染色及流氏細胞儀分析下我們發現TBC1D23會經由糖化作用、減少EGFR胞飲降解及增加EGFR回收下，進而增強EGFR在細胞膜的表現同時也增強VEGF-C的表現，同時在抑制EGFR後發現下游ERK這條路徑也被抑制了。因此TBC1D23是一個腫瘤相關蛋白，會利用EGFR/ERK的路徑調節VEGF-C的生成。
總結TBC1D23是一個腫瘤相關蛋白，在胰臟癌是預後不佳的指標。同時，在胰臟癌細胞中，TBC1D23增強EGFR在細胞膜的功能表現及下游EGFR/ERK這個訊息路徑去調控VEGF-C的生成

Pancreatic cancer remains one of the most devastating cancer types and the 5-year survival rate is only 5-6% worldwide. The poor prognosis is attributed to the late diagnosis, early dissemination, early metastasis, and resistance to chemotherapy. Understanding the mechanism of pancreatic cancer progression would provide a new treatment strategy. Pancreatic cancer usually arises from the pancreatic duct and often obliterates the pancreatic duct. Hence, the obstructed pancreatic duct could fill with abundant cancer-related proteins. First, we conducted the proteomic analysis in pancreatic juice of pancreatic cancer patients. TBC1D23 was found to be decreased in pancreatic juice after tumor resection. TBC1D23 is a GTPase activating protein and plays an important role during endosome-to-Golgi trafficking. Clinically, pancreatic tumor tissue microarrays and sera were used to determine TBC1D23 expression and its clinical impact. We found that high expression of TBC1D23 in cancer cells indicated worse prognosis and higher rate of lymph node metastasis. Also, the serum level of TBC1D23 was higher in cancer patients than in normal controls.
To study the biological role of TBC1D23 in pancreatic cancer, we established RNAi-based knockdown of TBC1D23 in pancreatic cancer cell lines (PANC-1 and BxPC-3) to discover its function in vitro and in vivo. TBC1D23 expression was higher in pancreatic cancer cell lines than the normal cells. The knockdown of TBC1D23 in PANC-1 cells inhibited cell growth, proliferation, and migration in vitro. In the orthotopic transplant mice model, knockdown of PANC-1 cells suppressed tumor growth and lymph node metastasis. Using the microarray analysis, vascular endothelial growth factor-C (VEGF-C) gene was found to be down-regulated in shTBC1D23 PANC-1 cells. TBC1D23-silenced PANC-1 cells showed decreased VEGF-C mRNA expression, protein expression, and secretion. PANC-1 control conditioned medium induced the tube formation of human lymphatic endothelial cells, whereas this effect was prevented by knockdown of TBC1D23.
VEGF-C is known to be regulated by epidermal growth factor receptor (EGFR) and EGFR is required for pancreatic tumorigenesis. In immunofluorescence staining and flow cytometry study, TBC1D23 increased EGFR cell membrane content through glycosylation and reduced EGF mediated EGFR endocytic degradation but promoted its recycling. Pharmacological inhibition of EGFR downstream ERK signaling reduced VEGF-C expression. Hence, TBC1D23 is an oncoprotein and regulates VEGF-C expression through the EGFR/ERK signaling pathway.
In conclusion, TBC1D23 was identified as an oncoprotein and indicated poor survival in pancreatic cancer patients. TBC1D23 may regulate the VEGF-C expression in pancreatic cancer cells through enhancing EGFR membranous expression and downstream EGFR/ERK signaling pathway.

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