Molecular mechanism of LKB1 in the invasion and metastasis of colorectal cancer

Chen,Yangyang; Liu,Yifei; Zhou,Yanhong; You,Hongxia

doi:10.3892/or.2018.6877

Molecular mechanism of LKB1 in the invasion and metastasis of colorectal cancer

Authors:
- Yangyang Chen
- Yifei Liu
- Yanhong Zhou
- Hongxia You
View Affiliations

Affiliations: Department of Gastroenterology, Hubei University of Science and Technology, Xianning, Hubei 437100, P.R. China, Department of Gastroenterology, Wuhan University Affiliated Zhongshan Hospital, Wuhan, Hubei 430032, P.R. China
Published online on: November 21, 2018 https://doi.org/10.3892/or.2018.6877
Pages: 1035-1044

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The occurrence of colorectal cancer (CRC) is associated with a variety of oncogenes and tumor‑suppressor genes. As a tumor‑suppressor gene, the liver kinase B1 gene (LKB1, also known as serine/threonine kinase 11, STK11) is closely related to tumor angiogenesis, invasion and metastasis, but its molecular mechanisms remain unclear. The aim of the present study was to investigate the effects of LKB1 on the invasion and metastasis of CRC, and to explore its molecular mechanisms. By detecting the expression of LKB1 in CRC, we can provide a reference index for diagnosing the depth of invasion and lymph node metastasis. Immunohistochemistry results indicated that LKB1 expression was strongly positive in normal colon tissue and that it inhibited the production of CRC. Immunocytochemical staining showed that the expression of LKB1 was significantly decreased in adenocarcinoma and mucinous adenocarcinoma tissues, and this reduced expression induced the invasion and metastasis of CRC. In the present study, LKB1 small interfering RNA (LKB1 siRNA) was transfected into LoVo cells to observe the effect of LKB1 on the invasion and metastasis of CRC. LKB1 silencing decreased the phosphorylation of AMP‑activated protein kinase (p‑AMPK) in its downstream pathway, which increased the phosphorylation of protein kinase B (p‑AKT) and promoted tumor cell proliferation, enhancing the migration and invasion of CRC. The present study also explored the role of metformin in the LKB1 signaling pathway. Metformin inhibits the invasion and metastasis of CRC by activating p‑AMPK, thereby inhibiting the activation of p‑AKT. These results suggest that LKB1 plays an important role in the invasion and metastasis of CRC by activating AMPK, negatively regulating the AKT signaling pathway and regulating gene expression. Mutation or deletion of LKB1 is expected to be a novel therapeutic target or clinical biomarker for the prevention of the invasion and metastasis of CRC.

View Figures

View References

1	Zhang M, Miao F, Huang R, Liu W, Zhao Y, Jiao T, Lu Y, Wu F, Wang X, Wang H, et al: RHBDD1 promotes colorectal cancer metastasis through the Wnt signaling pathway and its downstream target ZEB1. J Exp Clin Cancer Res. 37:222018. View Article : Google Scholar : PubMed/NCBI
2	Siegel RL, Miller KD and Jemal A: Cancer Statistics, 2017. CA Cancer J Clin. 67:7–30. 2017. View Article : Google Scholar : PubMed/NCBI
3	Hawley SA, Pan DA, Mustard KJ, Ross L, Bain J, Edelman AM, Frenguelli BG and Hardie DG: Calmodulin-dependent protein kinase kinase-beta is an alternative upstream kinase for AMP-activated protein kinase. Cell Metab. 2:9–19. 2005. View Article : Google Scholar : PubMed/NCBI
4	Dorward HS, Du A, Bruhn MA, Wrin J, Pei JV, Evdokiou A, Price TJ, Yool AJ and Hardingham JE: Pharmacological blockade of aquaporin-1 water channel by AqB013 restricts migration and invasiveness of colon cancer cells and prevents endothelial tube formation in vitro. J Exp Clin Cancer Res. 35:362016. View Article : Google Scholar : PubMed/NCBI
5	Slattery ML, Herrick JS, Mullany LE, Samowitz WS, Sevens JR, Sakoda L and Wolff RK: The co-regulatory networks of tumor suppressor genes, oncogenes, and miRNAs in colorectal cancer. Genes Chromosomes Cancer. 56:769–787. 2017. View Article : Google Scholar : PubMed/NCBI
6	Eshghifar N, Farrokhi N, Naji T and Zali M: Tumor suppressor genes in familial adenomatous polyposis. Gastroenterol Hepatol Bed Bench. 10:3–13. 2017.PubMed/NCBI
7	Tiainen M, Vaahtomeri K, Ylikorkala A and Mäkelä TP: Growth arrest by the LKB1 tumor suppressor: Induction of p21^WAF1/CIP1. Hum Mol Genet. 11:1497–1504. 2002. View Article : Google Scholar : PubMed/NCBI
8	Ylikorkala A, Rossi DJ, Korsisaari N, Luukko K, Alitalo K, Henkemeyer M and Mäkelä TP: Vascular abnormalities and deregulation of VEGF in Lkb1-deficient mice. Science. 293:1323–1326. 2001. View Article : Google Scholar : PubMed/NCBI
9	Hardie DG and Alessi DR: LKB1 and AMPK and the cancer-metabolism link-ten years after. BMC Biol. 11:362013. View Article : Google Scholar : PubMed/NCBI
10	Jeon SM and Hay N: The double-edged sword of AMPK signaling in cancer and its therapeutic implications. Arch Pharm Res. 38:346–357. 2015. View Article : Google Scholar : PubMed/NCBI
11	Larsen AK, de Gramont A, Poindessous V, Bouygues A, Ayadi M and Mésange P: Functions and clinical implications of autocrine VEGF signaling in colorectal cancer. Curr Colorect Cancer Rep. 9:270–277. 2013. View Article : Google Scholar
12	Deguchi A, Miyoshi H, Kojima Y, Okawa K, Aoki M and Taketo MM: LKB1 suppresses p21-activated kinase-1 (PAK1) by phosphorylation of Thr¹⁰⁹ in the p21-binding domain. J Biol Chem. 285:18283–18290. 2010. View Article : Google Scholar : PubMed/NCBI
13	Kim SW: The role of MicroRNAs in colorectal cancer. Korean J Gastroenterol. 69:206–211. 2017.(In Korean). View Article : Google Scholar : PubMed/NCBI
14	You HX, Zhou YH, Tan SY and She TH: Effects of silencing RIP1 with siRNA on the biological behavior of the LoVo human colon cancer cell line. Oncol Lett. 7:2065–2072. 2014. View Article : Google Scholar : PubMed/NCBI
15	He G, Zou L, Zhou L, Gao P, Qian X and Cui J: Cysteine-rich intestinal protein 1 silencing inhibits migration and invasion in human colorectal cancer. Cell Physiol Biochem. 44:897–906. 2017. View Article : Google Scholar : PubMed/NCBI
16	Zakikhani M, Dowling RJ, Sonenberg N and Pollak MN: The effects of adiponectin and metformin on prostate and colon neoplasia involve activation of AMP-activated protein kinase. Cancer Prev Res. 1:369–375. 2008. View Article : Google Scholar
17	Song X, Kim SY, Zhang L, Tang D, Bartlett DL, Kwon YT and Lee YJ: Role of AMP-activated protein kinase in cross-talk between apoptosis and autophagy in human colon cancer. Cell Death Dis. 5:e15042014. View Article : Google Scholar : PubMed/NCBI
18	Lipovka Y and Konhilas JP: AMP-activated protein kinase signalling in cancer and cardiac hypertrophy. Cardiovasc Pharm Open Access. 4:1542015.PubMed/NCBI
19	Xu H, Zhou Y, Coughlan KA, Ding Y, Wang S, Wu Y, Song P and Zou MH: AMPKα1 deficiency promotes cellular proliferation and DNA damage via p21 reduction in mouse embryonic fibroblasts. Biochim Biophys Acta. 1853:65–73. 2015. View Article : Google Scholar : PubMed/NCBI
20	Su KH, Yu YB, Hou HH, Zhao JF, Kou YR, Cheng LC, Shyue SK and Lee TS: AMP-activated protein kinase mediates erythropoietin-induced activation of endothelial nitric oxide synthase. J Cell Physiol. 227:3053–3062. 2012. View Article : Google Scholar : PubMed/NCBI
21	Monteverde T, Muthalagu N, Port J and Murphy DJ: Evidence of cancer-promoting roles for AMPK and related kinases. FEBS J. 282:4658–4671. 2015. View Article : Google Scholar : PubMed/NCBI
22	Wang Y, Wang B, Guerram M, Sun L, Shi W, Tian C, Zhu X, Jiang Z and Zhang L: Deoxypodophyllotoxin suppresses tumor vasculature in HUVECs by promoting cytoskeleton remodeling through LKB1-AMPK dependent Rho A activation. Oncotarget. 6:29497–29512. 2015.PubMed/NCBI
23	Altomare DA and Testa JR: Perturbations of the AKT signaling pathway in human cancer. Oncogene. 24:7455–7464. 2005. View Article : Google Scholar : PubMed/NCBI
24	Brugarolas J and Kaelin WG Jr: Dysregulation of HIF and VEGF is a unifying feature of the familial hamartoma syndromes. Cancer Cell. 6:7–10. 2004. View Article : Google Scholar : PubMed/NCBI
25	Amin MB, Edge SB, Greene FL, Byrd DR, Brookland RK, Washington MK, Gershenwald JE, Compton CC, Hess KR, Sullivan DC, et al: AJCC Cancer Staging Manual. (8th). 2018.
26	Dong SM, Kim KM, Kim SY, Shin MS, Na EY, Lee SH, Park WS, Yoo NJ, Jang JJ, Yoon CY, et al: Frequent somatic mutations in serine/threonine kinase 11/Peutz-Jeghers syndrome gene in left-sided colon cancer. Cancer Res. 58:3787–3790. 1998.PubMed/NCBI
27	Li W, Wang QL, Liu X, Dong SH, Li HX, Li CY, Guo LS, Gao JM, Berger NA, Li L, et al: Combined use of vitamin D3 and metformin exhibits synergistic chemopreventive effects on colorectal neoplasia in rats and mice. Cancer Prev Res. 8:139–148. 2015. View Article : Google Scholar
28	Zaafar DK, Zaitone SA and Moustafa YM: Role of metformin in suppressing 1,2-dimethylhydrazine-induced colon cancer in diabetic and non-diabetic mice: Effect on tumor angiogenesis and cell proliferation. PLoS One. 9:e1005622014. View Article : Google Scholar : PubMed/NCBI
29	Wu CY, Wang CJ, Tseng CC, Chen HP, Wu MS, Lin JT, Inoue H and Chen GH: Helicobacter pylori promote gastric cancer cells invasion through NF-kappaB and COX-2-mediated pathway. World J Gastroenterol. 11:3197–3203. 2005. View Article : Google Scholar : PubMed/NCBI