肺癌（Lung cancer）在台灣是第二常見且致死率第一名的癌症。將近有20%的病患是沒有明顯的症狀，並且有40%的病患在被診斷為肺癌時，都已經有癌細胞轉移的現象。腫瘤相關巨噬細胞（tumor-associated macrophages）是腫瘤微環境（tumor microenvironment）的成員之一，並且被認為具有促進腫瘤生長以及轉移的能力。曾有研究指出，肺癌相關巨噬細胞能夠透過類鐸受體2（Toll-like receptor 2）的訊息傳遞路徑，來分泌腫瘤壞死因子α（tumor necrosis factor-α）至腫瘤微環境中，進而促使肺癌細胞的轉移。近期有另外一篇研究指出，一個名為Rab37的小GTP水解酵素（small GTPase），能夠在巨噬細胞中調控類鐸受體4所誘發腫瘤壞死因子α的分泌。然而，是否Rab37也有參與以及調控肺癌相關巨噬細胞來分泌腫瘤壞死因子α仍然是未知的。在此篇研究中，我們發現在給予巨噬細胞小鼠Lewis肺癌細胞的條件培養液（Lewis lung carcinoma-conditioned medium）之後，透過類鐸受體2的訊息傳遞下，Rab37以及腫瘤壞死因子α的表現量皆有上升，並且也增加了腫瘤壞死因子α的分泌量。除此之外，在巨噬細胞中將Rab37進行基因下調（knockdown）的情況之下，會同時降低Lewis肺癌細胞的條件培養液所誘發腫瘤壞死因子α的表現量以及分泌量。然而，主要用來幫助腫瘤壞死因子α轉錄的轉錄因子NF-κB，在活化上並沒有受到影響。有趣的是，同樣在巨噬細胞中將Rab37進行基因下調（knockdown）的情況之下，相較於腫瘤壞死因子α，同為NF-κB所調控的介白素1β（interleukin-1β）在給予Lewis肺癌細胞的條件培養液之後轉錄量反而上升。這也代表Rab37在巨噬細胞中，似乎具有分別調控Lewis肺癌細胞的條件培養液所誘發腫瘤壞死因子α以及介白素1β轉錄的能力。除此之外，我們發現重組蛋白versican（recombinant versican），一個來自於肺癌細胞的可溶性蛋白質，在透過類鐸受體4的訊息路徑之下，也能夠使巨噬細胞誘發Rab37所調控腫瘤壞死因子α的表現以及分泌。最後，我們的發現對於Rab37如何在肺癌相關巨噬細胞中調控腫瘤壞死因子α的產生提供了一個新穎的機制，並且也提出了versican在這其中可能扮演的獨特角色。

Lung cancer is the number one cancer-related death in Taiwan and number two common cancer among men and women. There are almost 20% of patients without any symptom, and 40% of newly diagnosed patients with lung cancer already have metastasis. Tumor-associated macrophages (TAMs) are one of the members found in the tumor microenvironment (TME) and have the ability to promote tumor progression and metastasis. A previous study indicates that TAMs are able to secrete tumor necrosis factor-α (TNF-α) to foster lung cancer metastasis via toll-like receptor 2 (TLR2) signaling pathway. Recently, one report shows that Rab37, a small GTPase, is able to regulate TNF-α secretion from macrophages via TLR4 signaling pathway. However, it is unclear whether Rab37 controls TNF-α secretion from lung cancer-associated macrophages. Here we showed that Lewis lung carcinoma-conditioned medium (LCM) is able to upregulate the expression of both Rab37 and TNF-α, and hence increase the secretion of TNF-α from macrophages in a TLR2-dependent manner. Silencing of Rab37 in macrophages attenuates both LCM-induced TNF-α transcription and secretion; however, the activation of NF-κB, the major transcription factor of TNF-α, is not altered. Interestingly, in contrast to TNF-α, mRNA of IL-1β, another NF-κB-regulated cytokine, is upregulated in Rab37-silenced macrophages after LCM treatment, which indicates that Rab37 may differentially regulate the transcription of LCM-induced TNF-α and IL-1β. Furthermore, we found that recombinant versican (Vcan), which is reported as a lung cancer-derived soluble protein, is capable of triggering Rab37-mediated TNF-α expression and secretion in macrophages via TLR4 signaling. Our findings provide a novel mechanism of how Rab37 regulates the production of TNF-α in lung cancer-associated macrophages and a unique role of Vcan in Rab37-regulated TNF-α production in macrophages.

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