乳腺癌的發(fā)展和轉(zhuǎn)移與轉(zhuǎn)化生長因子-β（TGF-β）細(xì)胞因子的異常相關(guān)。在乳腺癌早期發(fā)展階段,，TGF-β呈現(xiàn)腫瘤抑制活性,，能抑制細(xì)胞的增殖，誘導(dǎo)腫瘤細(xì)胞死亡,，而在乳腺癌晚期階段,，TGF-β促進(jìn)腫瘤細(xì)胞的侵襲和轉(zhuǎn)移。
一直以來TGF-β的潛在致癌作用分子機(jī)制尚不完全清楚,，近日Daroqui MC 等研究人員在Oncol Rep雜志上發(fā)表論文證實(shí)了TGF-β信號(hào)在癌癥發(fā)生發(fā)展中的具體作用,，研究者使用LM3乳腺腺癌細(xì)胞株探討了TGF-β的致癌活性。激酶失活的TGF-β受體表達(dá)能降低腫瘤細(xì)胞基礎(chǔ)水平以及TGF-β誘導(dǎo)的腫瘤細(xì)胞的侵襲,。
信號(hào)傳導(dǎo)分析研究表明,，p38MAPK和MEK在TGF-β刺激腫瘤細(xì)胞運(yùn)動(dòng)和侵襲過程中發(fā)揮重要作用,。TGF-β破壞上皮細(xì)胞的肌動(dòng)蛋白結(jié)構(gòu)（肌動(dòng)蛋白結(jié)構(gòu)主要支持細(xì)胞間的粘連），并增加線性肌動(dòng)蛋白絲,。阻斷RAF-MEK信號(hào)通路能增強(qiáng)TGF-β誘導(dǎo)的肌動(dòng)蛋白表達(dá)上調(diào),，而p38MAPK的抑制劑卻能逆轉(zhuǎn)上述效應(yīng)。
此外,，TGF-β刺激基質(zhì)金屬蛋白酶MMP-9的分泌,。該研究表明，TGF-β有助于乳腺癌細(xì)胞的侵襲行為,。MEK-ERK和p38 MAPK通路是TGF-β致癌的關(guān)鍵所在,，也是干預(yù)治療乳腺癌的潛在靶標(biāo)。（生物谷：Bioon.com）
doi:10.3892/or.2012.1813
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TGF-β autocrine pathway and MAPK signaling promote cell invasiveness and in vivo mammary adenocarcinoma tumor progression.
Daroqui MC, Vazquez P, Bal de Kier Joffé E, Bakin AV, Puricelli LI.
Breast cancer progression and metastasis have been linked to abnormal signaling by transforming growth factor-β (TGF-β) cytokines. In early-stage breast cancers, TGF-β exhibits tumor suppressor activity by repressing cell proliferation and inducing cell death, whereas in advanced-stage tumors, TGF-β promotes invasion and metastatic dissemination. The molecular mechanisms underlying pro-oncogenic activities of TGF-β are not fully understood. The present study validates the role of TGF-β signaling in cancer progression and explores mediators of pro-oncogenic TGF-β activities using the LM3 mammary adenocarcinoma cell line, derived from a spontaneous murine mammary adenocarcinoma. Expression of kinase-inactive TGF-β receptors decreased both basal and TGF-β-induced invasion. Analysis of signal transduction mediators showed that p38MAPK and MEK contribute to TGF-β stimulation of cell motility and invasion. TGF-β disrupted the epithelial actin structures supporting cell-cell adhesions, and increased linear actin filaments. Moreover, MEK and p38MAPK pathways showed opposite effects on actin remodeling in response to TGF-β. Blockade of Raf-MEK signaling enhanced TGF-β induction of actin stress-fibers whereas p38MAPK inhibitors blocked this effect. A novel observation was made that TGF-β rapidly activates the actin nucleation Arp2/3 complex. In addition, TGF-β stimulated matrix metalloproteinase MMP-9 secretion via a MAPK-independent pathway. Experiments using syngeneic mice showed that kinase-inactive TGF-β receptors inhibit the first stages of LM3 tumor growth in vivo. Our studies demonstrate that autocrine TGF-β signaling contributes to the invasive behavior of mammary carcinoma cells. Moreover, we show that both MAPK-dependent and -independent pathways are necessary for TGF-β-induced effects. Therefore, MEK-ERK and p38 MAPK pathways are potential venues for therapeutic intervention in pro-oncogenic TGF-β signaling.
