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.
LKB1 (also known as STK11) is a potent tumor suppressor in solid tumors, such as melanoma and lung adenocarcinoma, but inactivation in hematopoietic cells causes cell death without signs of tumorigenesis.
Multivariate COX regression analysis indicated that LKB1 promoter methylation was an independent prognostic factor for overall survival in patients with melanoma.
Simultaneous Cdkn2a and Lkb1 inactivation in Braf(V600E) melanocytes results in activation of both mTORC1 and mTORC2/Akt, inducing rapid melanoma formation in mice.
Inhibition of the LKB1-MARK pathway facilitated invasive motility, suggesting that loss of the ability to sense inhibitory matrix cues may promote melanoma invasion.
The STK11/LKB1 gene encodes a ubiquitously expressed serine/threonine kinase that is mutated in multiple sporadic cancers including non-small cell lung carcinomas, pancreatic cancers, and melanomas.
Furthermore, expression of a phosphorylation-deficient mutant of LKB1 allows activation of AMPK and inhibits melanoma cell proliferation and anchorage-independent cell growth.
Although PJS patients are not known to have an excess of skin tumors, if the freckles of PJS patients are actually small, benign tumors, LKB1/STK11 mutations must provide these lesions with a selective advantage, and similar mutations might also give a selective advantage to related malignant tumors, such as melanomas.
Germline mutations in BRCA2 have been shown to predispose to both breast and pancreatic cancer, germline mutations in p16 to melanoma and pancreatic cancer (the FAMMM syndrome), and genetic mutations in STK11/LKB1 to pancreatic cancer in patients with the Peutz-Jeghers Syndrome (PJS).