Crabp2 透過 HuR 以及 Integrin β1/FAK/ERK 訊 息傳導促進肺癌細胞轉移;Crabp2 Promotes Metastasis of Lung Cancer Cells via HuR and Integrin β1/FAK/ERK Signaling

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Title:	Crabp2 透過 HuR 以及 Integrin β1/FAK/ERK 訊息傳導促進肺癌細胞轉移;Crabp2 Promotes Metastasis of Lung Cancer Cells via HuR and Integrin β1/FAK/ERK Signaling
Authors:	吳俊誼;Wu, Jun-I
Contributors:	生命科學系
Keywords:	肺癌;轉移;Crabp2;HuR;Lung cancer;Metastasis;Crabp2;HuR
Date:	2019-03-29
Issue Date:	2019-04-02 14:22:03 (UTC+8)
Publisher:	國立中央大學
Abstract:	許多類型的癌症腫瘤已經發現會高表現 CRABP2 並且關聯到病人的較差存活率。肺癌腫瘤也已經發現會高表現 CRABP2 ，但是 CRABP2 在肺癌轉移中的角色仍不清楚。本研究發現 Crabp2 在高轉移能力的 C10F4 肺癌細胞的表現會高過低轉移能力的肺癌細胞。我們發現 CRABP2 在臨床檢體的高表現與淋巴轉移，較差的存活率以及較高的復發率有關。抑制 Crabp2 的表現量會降低肺癌細胞的移動，侵襲，懸浮狀態下的存活率，以及老鼠模式中的轉移能力。在免疫沉澱法中， Crabp2 能夠與 HuR 共同沉澱。高表現 Crabp2 可以增加 HuR 的表現量，並且HuR可以促進 integrin β1 表現以及 FAK 和 ERK 的磷酸化。抑制 HuR 或是 integrin β1 的表現，亦或是對細胞處理 FAK 或 ERK 的抑制劑都能夠降低 Crabp2 促進肺癌細胞移動，侵襲，以及懸浮狀態下存活率的能力。另外，與單獨處理 gemcitbine 或是 irinotecan 相比，抑制 Crabp2 能夠進一步抑制肺癌細胞的生長。 CRABP2 在人類腫瘤檢體中的表現量與細胞壓力 (stress) 標記分子 CHOP 的表現量呈現正相關。因此，我們的研究顯示出 Crabp2 在肺癌細胞轉移中扮演促進的角色。 CRABP2 可以作為一個潛在的預後標記分子，並且標靶 CRABP2 可以作為一個潛在的抑制肺癌轉移策略。此外，我們也發現了間隙蛋白 Connexin 30.3 (Cx30.3, GJB4) 會促進肺癌細胞的轉移能力，因此我們也回顧了連接蛋白 (gap junction proteins, connexins)在癌症轉移中的角色。間隙蛋白是一種四次穿膜的蛋白，能夠在相鄰的兩個細胞中間形成間隙連接 (gap junction) 並且因此促進細胞間的溝通 (gap junctional intercellular communication; GJIC) 。傳統上認為間隙蛋白的角色在於形成半通道 (hemichannels) 後進一步組裝成間隙連接，並以此促進離子以及小分子的傳遞。許多研究中均觀察到原位腫瘤細胞中的間隙蛋白表現量下降或是移位到細胞質內，因而造成 GJIC 的缺失。因此，間隙蛋白一般被認為會抑制腫瘤。然而，近年的研究發現了間隙蛋白在癌症轉移中可能還扮演不同的角色：在病人的轉移組織切片中發現了 Connexin 43 (Cx43, GJA1) 以及 Connexin 26 (Cx26, GJB2) 的表現量以及它們出現在細胞膜的比率相較於原位腫瘤有所上升。 Cx43 以及 Cx26 所調控的 GJIC 能夠促進癌細胞的移動能力以及對於胸腔內皮細胞的貼附。許多研究也報導了間隙蛋白在不同癌症類型中的表現以及功能。在這裡我們聚焦回顧並且討論 1) 間隙蛋白在臨床檢體上的表現與病人預後的關聯性，2) 間隙蛋白在癌症轉移以及抗藥性中的角色，以及3) 將標靶間隙蛋白的分子作為抑制轉移藥物的應用以及考量。總結來說，間隙蛋白可以做為潛在的癌症預後標記分子，以及開發干擾癌症轉移以及抗藥性的標的。;Increased CRABP2 levels have been found in various types of cancer, and are associated with poor patients’ survival. Although CRABP2 is found to be overexpressed in lung cancer, its role in metastasis of lung cancer is unclear. In this study, Crabp2 was overexpressed in high-metastatic C10F4 than low-metastatic lung cancer cells. Analysis of clinical samples revealed that high CRABP2 levels were correlated with lymph node metastases, poor overall survival, and increased recurrence. Knockdown of Crabp2 decreased migration, invasion, anoikis resistance, and in vivo metastasis. Crabp2 was co-immunoprecipitated with HuR, and overexpression of Crabp2 increased HuR levels, which promoted integrin β1/FAK/ERK signaling. Inhibition of HuR or integrin β1/FAK/ERK signaling reversed the promoting effect of Crabp2 in migration, invasion, and anoikis resistance. Knockdown of Crabp2 further inhibited the growth of cancer cells as compared with that by gemcitabine or irinotecan alone. The expression of Crabp2 in human lung tumors was correlated with stress marker CHOP. In conclusion, our findings have identified the promoting role of Crabp2 in anoikis resistance and metastasis. CRABP2 may serve as a prognostic marker and targeting CRABP2 may be exploited as a modality to reduce metastasis. In parallel, our laboratory has found the promoting role of Connexin 30.3 (Cx30.3, GJB4) in metastasis of lung cancer cells, and thus we reviewed the role of gap junction protein connexins in cancer metastasis. Connexin, a four-pass transmembrane protein, contributes to the assembly of gap junctions among neighboring cells and thus facilitates gap junctional intercellular communication (GJIC). Traditionally, the roles of connexins were thought to mediate formation of hemichannels and GJIC assembly for transportation of ions and small molecules. Many studies have observed loss of GJIC, due to reduced expression or altered cytoplasmic localization of connexins, in primary tumor cells. Connexins are generally considered tumor-suppressive. However, recent studies of clinical samples suggested a different role of connexins in that expression levels and membrane localization of connexins, including Connexin 43 (Cx43, GJA1) and Connexin 26 (Cx26, GJB2), were found to be enhanced in metastatic lesions of cancer patients. Cx43- and Cx26-mediated GJIC was found to promote cancer cell migration and adhesion to the pulmonary endothelium. Regulatory circuits involved in the induction of connexins and their functional effects have also been reported in various types of cancer. Here we focus on the recent findings in the correlation between the expression of connexins and patients’ prognosis, their roles in metastasis and chemoresistance, as well as the implications and concerns of using connexin-targeting drugs as anti-metastatic therapeutics. Overall, connexins may serve as biomarkers for cancer prognosis and as therapeutic targets for intervening metastasis and chemoresistance.
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