LKB1 loss cooperating with BRAF V600E promotes melanoma cell invasion and migration by up-regulation MMP-2 via PI3K/Akt/mTOR pathway.
LKB1 loss cooperating with BRAF V600E promotes melanoma cell invasion and migration by up-regulation MMP-2 via PI3K/Akt/mTOR pathway.
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DOI：
10.18632/oncotarget.22943
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发表时间：
2017-12-26
期刊：
影响因子：
--
通讯作者：
Luo D
中科院分区：
文献类型：
--
作者：
Zhang W;Yin L;Song G;Han X;Yin Z;Luo D
丝氨酸/苏氨酸激酶LKB1，作为一种肿瘤抑制因子，已经在几种散发性癌症中被报道。然而，LKB1的缺失如何促进黑色素瘤的侵袭和转移仍不完全清楚。在本研究中，我们通过RNA干扰分别在BRAF突变黑色素瘤细胞和野生型黑色素瘤细胞中抑制了LKB1的表达。通过伤口划痕试验、Transwell试验等一系列实验，我们发现LKB1失活协同BRAF V600E导致黑色素瘤细胞更具侵袭性。而LKB1缺失或BRAF V600E的单一改变均不能增强黑色素瘤细胞的侵袭能力。在机制上，LKB1与BRAF V600E的缺失协同作用导致PI3K/Akt/mTOR信号通路激活，并显著上调MMP2的表达。此外，在存在BRAF V600E的情况下，人黑色素瘤组织中LKB1的表达与基质金属蛋白酶-2的表达呈负相关。因此，我们的发现可能解释了LKB1在黑色素瘤中作为肿瘤抑制因子的作用，并通过联合靶向BRAF和LKB1来治疗黑色素瘤的新策略。
The serine/threonine kinase LKB1, act as a tumor suppressor, has been reported in several sporadic cancers. However, how the loss of LKB1 promotes melanoma invasion and metastasis remains incompletely understood. In this study, we inactivated LKB1expression by RNA interference in BRAF mutation and wild type melanoma cells respectively. We found LKB1 inactivation cooperate with BRAF V600E lead to melanoma cells more aggressive by a series of experiments including wound scratch test, Transwell assay. While single alteration, either LKB1 loss or BRAF V600E, fails to enhance melanoma cells invasion ability. Mechanistically, LKB1 loss synergism with BRAF V600E resulted in the activation of the PI3K/Akt/mTOR signaling pathway and significant up-regulation expression of MMP-2. In addition, LKB1 expression in human melanoma tissues was negatively associated with MMP-2 expression in the presence of BRAF V600E. Thus, our findings indicate a probable explanation on LKB1 function as a tumor suppressor in melanoma and a new therapeutic strategy for melanoma by targeting on BRAF and LKB1 together.
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DOI：
10.1073/pnas.1317577110
发表时间：
2013-11-05
影响因子：
11.1
作者：
Yuan, Ping;Ito, Koichi;Zheng, Bin
通讯作者：
Zheng, Bin
影响因子：
50.3
作者：
Liu W;Monahan KB;Pfefferle AD;Shimamura T;Sorrentino J;Chan KT;Roadcap DW;Ollila DW;Thomas NE;Castrillon DH;Miller CR;Perou CM;Wong KK;Bear JE;Sharpless NE
通讯作者：
Sharpless NE
影响因子：
3.2
作者：
Zhao RX;Xu ZX
通讯作者：
Xu ZX
影响因子：
50.3
作者：
Damsky W;Micevic G;Meeth K;Muthusamy V;Curley DP;Santhanakrishnan M;Erdelyi I;Platt JT;Huang L;Theodosakis N;Zaidi MR;Tighe S;Davies MA;Dankort D;McMahon M;Merlino G;Bardeesy N;Bosenberg M
通讯作者：
Bosenberg M
影响因子：
8.8
作者：
Lu H;Liu S;Zhang G;Kwong LN;Zhu Y;Miller JP;Hu Y;Zhong W;Zeng J;Wu L;Krepler C;Sproesser K;Xiao M;Xu W;Karakousis GC;Schuchter LM;Field J;Zhang PJ;Herlyn M;Xu X;Guo W
通讯作者：
Guo W