Loss of Stk11/Lkb1 Expression in Pancreatic and Biliary Neoplasms

Şahin, Fikret; Maitra, Anirban; Argani, Pedram; Sato, Norihiro; Maehara, Naoki; Montgomery, Elizabeth A.; Goggins, Michael; Hruban, Ralph H.; Su, Gloria H.

doi:10.1097/01.mp.0000075645.97329.86

Cited by 103 publications

(70 citation statements)

References 23 publications

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“…We also found INPP4B was not detected in a significant number of normal cervical tissues. The low expression of INPP4B in a certain proportion of normal cervix is analogous to that of LKB1, a tumour suppressor upstream of INPP4B, which also displays weak or no expression in normal colorectal, pancreas and cervical tissues 16, 26, 27. We speculate that low expression of INPP4B could be due to lack of tumorigenesis‐associated stresses to INPP4B in normal cervical cells.…”

Section: Discussionmentioning

confidence: 84%

INPP4B restrains cell proliferation and metastasis via regulation of the PI3K/AKT/SGK pathway

Chen

Sun

et al. 2018

J Cellular Molecular Medi

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Cervical cancer continues to be among the most frequent gynaecologic cancers worldwide. The phosphoinositide 3‐kinase (PI3K)/protein kinase B (AKT) pathway is constitutively activated in cervical cancer. Inositol polyphosphate 4‐phosphatase type II (INPP4B) is a phosphoinositide phosphatase and considered a negative regulatory factor of the PI3K/AKT pathway. INPP4B has diverse roles in various tumours, but its role in cervical cancer is largely unknown. In this study, we investigated the role of INPP4B in cervical cancer. Overexpression of INPP4B in HeLa, SiHa and C33a cells inhibited cell proliferation, metastasis and invasiveness in CCK‐8, colony formation, anchorage‐independent growth in soft agar and Transwell assay. INPP4B reduced the expression of some essential proteins in the PI3K/AKT/SGK3 pathway including p‐AKT, p‐SGK3, p‐mTOR, phospho‐p70S6K and PDK1. In addition, overexpression of INPP4B decreased xenograft tumour growth in nude mice. Loss of INPP4B protein expression was found in more than 60% of human cervical carcinoma samples. In conclusion, INPP4B impedes the proliferation and invasiveness of cervical cancer cells by inhibiting the activation of two downstream molecules of the PI3K pathway, AKT and SGK3. INPP4B acts as a tumour suppressor in cervical cancer cells.

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Section: Discussionmentioning

confidence: 84%

INPP4B restrains cell proliferation and metastasis via regulation of the PI3K/AKT/SGK pathway

Chen

Sun

et al. 2018

J Cellular Molecular Medi

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“…LKB1 promoter hypermethylation has been reported in nearly 50% of sporadic papillary breast cancers and 12% of testicular cancers, whereas LKB1 promoter hypermethylation appears uncommon or absent in other types of sporadic breast cancers, as well as colon, gastric and pancreatic cancers (Esteller et al, 2000). In addition, loss of LKB1 expression has been noted in sporadic endometrial cancers (Contreras et al, 2008), neuroendocrine lung cancers and pancreatic cancers (Sahin et al, 2003;Amin et al, 2008).…”

Section: Peutz-jeghers Syndrome and Human Cancer Geneticsmentioning

confidence: 99%

LKB1; linking cell structure and tumor suppression

2008

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Germ line mutations in the LKB1 tumor suppressor gene are associated with the Peutz-Jeghers polyposis and cancer syndrome. Somatic mutations in Lkb1 are observed in sporadic pulmonary, pancreatic and biliary cancers and melanomas. The LKB1 serine-threonine kinase functionally and biochemically links control of cellular structure and energy utilization through activation of the AMPK family of kinases. Lkb1 regulates cell polarity through downstream kinases including AMPKs, MARKs and BRSKs, and nutrient utilization and cellular metabolism through the AMPK-mTOR pathway. LKB1 has been shown to affect normal chromosomal segregation, TGF-b signaling in the mesenchyme and WNT and p53 activity. Although each of the LKB1-dependent processes and downstream pathways have been individually delineated through work across a range of experimental systems, how they relate to Lkb1's role as a tumor suppressor remains to be fully explored and elucidated. The recent development of mouse cancer models harboring engineered mutations in Lkb1 have offered insights into how LKB1 may be functioning to restrain tumorigenesis and how its role as a master regulator of polarity and metabolism could contribute to its tumor suppressor function.

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“…6,7 Moreover, various sporadic cancers are also associated with the loss of LKB1, implicating the general role of LKB1 in tumor suppression. [8][9][10] As point mutations of LKB1 found in PJS mostly reside in the highly conserved kinase domain, it is very likely that the kinase activity of LKB1 is essential for its tumor suppressive function. 11,12 Since the discovery of LKB1 in 1998, various functions of LKB1 molecule were suggested to be responsible for its tumor-suppressing activity -such as inhibition of cell cycle progression, cell growth retardation, apoptotic cell death, and cell polarity control.…”

Section: Introductionmentioning

confidence: 99%

JNK pathway mediates apoptotic cell death induced by tumor suppressor LKB1 in Drosophila

et al. 2005

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Although recent progresses have unveiled the diverse in vivo functions of LKB1, detailed molecular mechanisms governing these processes still remain enigmatic. Here, we showed that Drosophila LKB1 negatively regulates organ growth by caspase-dependent apoptosis, without affecting cell size and cell cycle progression. Through genetic screening for LKB1 modifiers, we discovered the JNK pathway as a novel component of LKB1 signaling; the JNK pathway was activated by LKB1 and mediated the LKB1-dependent apoptosis. Consistently, LKB1-null mutant was defective in embryonic apoptosis and displayed a drastic hyperplasia in the central nervous system; these phenotypes were fully rescued by ectopic JNK activation as well as wild-type LKB1 expression. Furthermore, inhibition of LKB1 resulted in epithelial morphogenesis failure, which was associated with a decrease in JNK activity. Collectively, our studies unprecedentedly elucidate JNK as the downstream mediator of the LKB1-dependent apoptosis, and provide a new paradigm for understanding the diverse LKB1 functions in vivo.

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Loss of Stk11/Lkb1 Expression in Pancreatic and Biliary Neoplasms

Cited by 103 publications

References 23 publications

INPP4B restrains cell proliferation and metastasis via regulation of the PI3K/AKT/SGK pathway

INPP4B restrains cell proliferation and metastasis via regulation of the PI3K/AKT/SGK pathway

LKB1; linking cell structure and tumor suppression

JNK pathway mediates apoptotic cell death induced by tumor suppressor LKB1 in Drosophila

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