Rab家族是小分子的GTP的分解酶，已知活化態Rab37主導TIMP1(tissue inhibitor of metalloproteinase 1)的釋放，以抑制細胞外MMP9 (matrix metalloproteinase 9)的活性，而降低肺癌細胞的行動力。此外IL-1可以藉由細胞自噬(autophagy)的非傳統路徑被釋放，而Sec22b參與在此釋放過程中， Sec22b蛋白是胞器運輸相關syntaxin5 SNARE複合體之一員，為清除胞自噬小體內(autophagosome)物質所必需。本實驗室蛋白質體分析後揭示Rab37及Sec22b二蛋白都包含在表現活化態Rab37肺癌細胞(CL1-5 Q89L)之自噬小體中，顯示此二蛋白均參與在細胞自噬的過程。已知另一個SNARE蛋白成員VAMP8參與細胞自噬的過程中並為活化態Rab37可能之執行蛋白 (effector)。本研究擬釐清自噬反應是否經由Sec22b及VAMP8參與Rab37主導的TIMP1分泌及癌化現象。首先，我們純化出H460肺癌細胞之自噬小體，並發現Sec22b、Rab37、VAMP8及TIMP1都存在於自噬小體中，顯示自噬作用、Sec22b及VAMP8參與Rab37主導之TIMP1分泌過程中。然而，在H460肺癌細胞中當Rab37蛋白之表現被抑制時，飢餓 (starvation)之刺激無法促進TIMP1及LC3蛋白之共位 (colocalization)及TIMP1之釋放，顯示Rab37主導TIMP1之分泌。至於自噬作用是否會影響Sec22b及VAMP8之表達，結果顯示自噬反應不影響Sec22b的表現量，但抑制自噬反應會降低VAMP8的表現量及TIMP1的釋放量。藉由共軛焦顯微鏡觀察發現飢餓刺激活化Rab37並促進自噬反應時，胞內之Sec22b及Rab37與LC3以及Rab37與VAMP8均形成更多的共位現象，而Sec22b及Rab37的共位現象廣泛存在細胞質中但不受飢餓處理的影響，以上之結果推論Sec22b及Rab37可能位於同一胞器上，而在飢餓情況下會促進Sec22b-Rab37胞器與自噬小體以及Rab37之胞器與溶酶體(lysosome)的接觸。當抑制Sec22b之表現量時，Rab37及LC3的共位顯著的下降，伴隨著LC3 II表現量及TIMP1分泌量下降，以及促進肺癌細胞之爬行及侵入能力，因此，我們推論Sec22b可能經由與自噬小體上的SNARE protein - Stx17的交互作用影響Rab37胞器及自噬小體之融合以及抑制肺癌細胞的移動。而抑制VAMP8之表現量則會促進肺癌細胞之增生、群落形成及侵入之能力。進一步觀察Sec22b蛋白及細胞自噬作用在肺癌病人檢體中的角色，結果顯示在腫瘤部分有較高比率之p62的累積(代表低自噬反應)，同時p62累積與肺癌細胞轉移到臨近淋巴是有顯著相關性，而Sec22b低表現與癌症轉移相關，顯示低自噬反應及低Sec22b蛋白表現導致之低TIMP1釋放可能造成肺癌細胞轉移。總結之，本研究揭示Sec22b會促進Rab37胞器與自噬小體的融合，進而增進Rab37胞器在自噬反應的協助下釋放TIMP1，並抑制肺癌細胞之移動力。而VAMP8不會影響Rab37胞器與自噬小體的融合及TIMP1的釋放，但會降低自噬作用之降解能力，因而增強肺癌細胞致癌性。

Rab37, a small GTPase, is known for the exocytosis of TIMP1 (tissue inhibitor of metalloproteinase 1) which leads to inhibition of MMP9 (matrix metalloproteinase 9) activity and decrease of cancer cell motility. Autophagy participates in IL-1secretion through an unconventional secretory pathway by which IL-1 was recruited to the LC3II protein containing vesicles mediated by Sec22b. Sec22b, a component of syntaxin5 SNARE complex, is responsible for vesicle transportation and the clearance of autophagic cargoes. We previously identified Rab37 and Sec22b proteins in the purified autophagosomes from lung cancer CL1-5 Q89L cells by proteomics analysis, indicating that these two proteins are involved in autophagic progression. Moreover, VAMP8, another SNARE protein and the effector of active form Rab37, is involved in autophagosome and lysosome fusion. Here, we clarified the roles of Sec22b and VAMP8 in autophagy as well as in Rab37-mediated TIMP1 secretion and tumorigenesis. We detected Sec22b, Rab37, VAMP8, and TIMP1 in the purified autophasosomes from lung cancer H460 cells, indicating that Sec22b and VAMP8 may participate in Rab37- mediated TIMP1 secretion through autophagy. However, we found that starvation treatment could not induce the colocalization of TIMP1 containing vesicles and autophagosomes when Rab37 was silenced, indicating Rab37 is the upstream regulator of TIMP1 secretion. We further reveal that autophagy has no effect on Sec22b expression. Differently, TIMP1 secretion was positively regulated by autophagic activity, and VAMP8 level fluctuated with LC3 II level. Image analyze reveal increased colocalization of Sec22b-LC3, Rab37-LC3 as well as VAMP8-Rab37 under starvation conditions. Colocalization of Sec22b and Rab37 was detected in the cytoplasm but not affected by starvation, indicating that Rab37 and Sec22b may anchor on the same vesicle in the cytoplasm. The colocalization of Sec22b-Rab37 vesicle and autophagosome and Rab37 vesicle and lysosome was increased by starvation. When Sec22b expression was silenced, LC3 II expression, TIMP1 secretion, and the colocalization of Rab37 and LC3 decreased. It indicates that the fusion of Rab37 anchored vesicle with autophagosome is affected by Sec22b through Stx17 which anchored on autophagosome and Sec22b interaction. Functional analysis reveal that Sec22b has negative effect on cell motility, and VAMP8 shows suppressive effect on cell proliferation, colony formation and cell motility. Analysis of lung cancer patient specimens reveals high percentage of p62 accumulation (representing low autophagic activity) in the tumor parts and correlation with lung cancer tumor spreading to regional lymph nodes (N stage). Low expression of Sec22b correlates with cell metastasis (M stage) of lung cancer patients. In conclusion, we disclose that colocalization of Rab37 anchored vesicles with autophagosome, TIMP1 secretion, and cell motility are affected by Sec22b. But, colocalization of Rab37 anchored vesicles with autophagosome and TIMP1 secretion are not affected by VAMP8. VAMP8 suppresses cell proliferation and colony formation.

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