Abstract
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.
Highlights
Malignant melanoma (MM) is a type of cancer originated from uncontrolled proliferation of melanocytes
To investigate the role of LKB1 loss in migration and invasion of melanoma cell lines, LKB1 was knocked down in MeWo human melanoma cells (BRAF wild type) by small interfering RNA targeting on LKB1, and non-specific siRNA, which has no target in human transcriptome, was used as a negative control. 48 hours after transfection, the efficiency and specificity of LKB1 knockdown were verified by west-blotting and qRT-PCR
BRAF V600E is the most common mutation found in melanoma; we analyzed the effect of LKB1 loss on migration and invasion of the melanoma cell lines in the presence of BRAF V600E
Summary
Malignant melanoma (MM) is a type of cancer originated from uncontrolled proliferation of melanocytes. V-Raf murine sarcoma viral oncogene homolog B1 (BRAF) is a member of the RAF protein kinase family and an intermediate in the RAS-RAF-MEKERK signaling pathway It has been found mutated in more than 50% of melanomas with the most common type of valine-to glutamic acid substitution at residue 600(V600E) [4]. Despite of the successes of BRAF inhibitors in therapy of melanoma patients with BRAF mutation, there are only half of these patients demonstrated effective in the process of treatment and almost all patients will be eventually resistant to inhibitors Overall, these facts indicate that oncogenic mutation of BRAF is insufficient for melanoma transformation and it may probably accompanied by one or more other genes alterations during tumor progression [6, 7]. Several researchers have reported the similar cooperation events in BRAF mutated tumors
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