Effects of Signaling Pathway on Development of Hepatocellular Carcinoma_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

 LIXun , MENGWen-bo , BAIZhongtian , YANJu , ZHANGLei , ZHOUWen-ce

Department of Surgery Ⅱ, The First Hospital of Lanzhou University, Hepatopancreatobiliary Surgery Insititute of Gansu Province, Lanzhou 730000, Gansu Province, China;

Corresponding author：

LIXun, Email: lxdr21@126.com

Keywords：

Signaling pathway; Hepatocellular carcinoma; Hepatocarcinogenesis

DOI：

10.7507/1007-9424.20140220

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To investigate the effects of signaling pathway about the EGFR, MAPK, IKB/NF-κB, PI3K/Akt, WNT/beta-catenin, and the Hedgehog in development of hepatocellular carcinoma(HCC). Methods The related literatures about the molecular genetic mechanism of signaling pathways were reviewed. Results In the occurrence and development of HCC, the EGFR, MAPK, IKB/NF-κB, PI3K/Akt, WNT/β-catenin, and Hedgehog signaling pathways not only interweaver with each other complexly, but also interact with each other, and some tumor markers, anticancer genes, proto-oncogenes, and miRNA may have synergistic effects for the occurrence of HCC. Conclusion The abnormal changes of molecular signaling pathways is a necessary condition for the occurrence and development of tumor, and there is considerable cross-talk and redundancy to many signaling pathways.

Citation： LIXun, MENGWen-bo, BAIZhongtian, YANJu, ZHANGLei, ZHOUWen-ce. Effects of Signaling Pathway on Development of Hepatocellular Carcinoma. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2014, 21(7): 916-920. doi: 10.7507/1007-9424.20140220 Copy

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2.	Kim Y, Kim J, Lee HD, et al. Spectrum of EGFR gene copy number changes and KRAS gene mutation status in Korean triple negative breast cancer patients[J]. PLoS One, 2013, 8(10): e79014.
3.	Glaysher S, Bolton LM, Johnson P, et al. Targeting EGFR and PI3K pathways in ovarian cancer[J]. Br J Cancer, 2013, 109(7):1786-1794.
4.	Walker F, Abramowitz L, Benabderrahmane D, et al. Growth factor receptor expression in anal squamous lesions:modifications associated with oncogenic human papillomavirus and human immunodeficiency virus[J]. Hum Pathol, 2009, 40(11):1517-1527.
5.	Jiang L, Huang J, Morehouse C, et al. Low frequency KRAS mutations in colorectal cancer patients and the presence of multiple mutations in oncogenic drivers in non-small cell lung cancer patients[J]. Cancer Genet, 2013, 206(9-10):330-339.
6.	Oh HS, Eom DW, Kang GH, et al. Prognostic implications of EGFR and HER-2 alteration assessed by immunohistochemistry and silver in situ hybridization in gastric cancer patients following curative resection[J]. Gastric Cancer, 2013 Aug 17.[Epub ahead of print].
7.	Narayanan R, Kim HN, Narayanan NK, et al. Epidermal growth factor-stimulated human cervical cancer cell growth is associated with EGFR and cyclin D1 activation, independent of COX-2 expression levels[J]. Int J Oncol, 2012, 40(1):13-20.
8.	Yoshioka S, Takemasa I, Nagano H, et al. Molecular prediction of early recurrence after resection of hepatocellular carcinoma[J]. Eur J Cancer, 2009, 45(5):881-889.
9.	Farber E, Sarma DS. Hepatocarcinogenesis:a dynamic cellular perspective[J]. Lab Invest, 1987, 56(1):4-22.
10.	Farazi PA, DePinho RA. Hepatocellular carcinoma pathogenesis: from genes to environment[J]. Nat Rev Cancer, 2006, 6(9): 674-687.
11.	Calvisi DF, Ladu S, Gorden A, et al. Mechanistic and prognostic significance of aberrant methylation in the molecular pathogenesis of human hepatocellular carcinoma[J]. J Clin Invest, 2007, 117(9):2713-2722.
12.	Pearson G, Robinson F, Beers Gibson T, et al. Mitogen-activated protein (MAP) kinase pathways:regulation and physiological functions[J]. Endocr Rev, 2001, 22(2):153-183.
13.	Sun X, Han L, Seth P, et al. Disordered purinergic signaling and abnormal cellular metabolism are associated with development of liver cancer in Cd39/ENTPD1 null mice[J]. Hepatology, 2013, 57(1):205-216.
14.	Kaposi-Novak P, Lee JS, Gòmez-Quiroz L, et al. Met-regulated expression signature defines a subset of human hepatocellular carcinomas with poor prognosis and aggressive phenotype[J]. J Clin Invest, 2006, 116(6):1582-1595.
15.	Cariani E, Lasserre C, Seurin D, et al. Differential expression of insulin-like growth factor II mRNA in human primary liver cancers, benign liver tumors, and liver cirrhosis[J]. Cancer Res, 1988, 48(23):6844-6849.
16.	Baba M, Yamamoto R, Iishi H, et al. Ha-ras mutations in N-nitrosomorpholine-induced lesions and inhibition of hepatocarcinogenesis by antisense sequences in rat liver[J]. Int J Cancer, 1997, 72(5):815-820.
17.	Calvisi DF, Pinna F, Pellegrino R, et al. Ras-driven proliferation and apoptosis signaling during rat liver carcinogenesis is under genetic control[J]. Int J Cancer, 2008, 123(9):2057-2064.
18.	Weihrauch M, Benicke M, Lehnert G, et al. Frequent k-ras-2 mutations and p16(INK4A) methylation in hepatocellular carcinomas in workers exposed to vinyl chloride[J]. Br J Cancer, 2001, 84(7):982-989.
19.	Lin YW, Yang JL. Cooperation of ERK and SCFSkp2 for MKP-1 destruction provides a positive feedback regulation of proliferating signaling[J]. J Biol Chem, 2006, 281(2):915-926.
20.	Frau M, Feo F, Pascale RM. Pleiotropic effects of methionine adenosyltransferases deregulation as determinants of liver cancer progression and prognosis[J]. J Hepatol, 2013, 59(4):830-841.
21.	Calvisi DF, Pinna F, Ladu S, et al. Forkhead box M1B is a determinant of rat susceptibility to hepatocarcinogenesis and sustains ERK activity in human HCC[J]. Gut, 2009, 58(5):679-687.
22.	Calvisi DF, Pinna F, Meloni F, et al. Dual-specificity phosphatase 1 ubiquitination in extracellular signal-regulated kinase-mediated control of growth in human hepatocellular carcinoma[J]. Cancer Res, 2008, 68(11):4192-4200.
23.	Fantappiè O, Masini E, Sardi I, et al. The MDR phenotype is associated with the expression of COX-2 and iNOS in a human hepatocellular carcinoma cell line[J]. Hepatology, 2002, 35(4): 843-852.
24.	Calvisi DF, Pinna F, Ladu S, et al. Aberrant iNOS signaling is under genetic control in rodent liver cancer and potentially prognostic for the human disease[J]. Carcinogenesis, 2008, 29(8): 1639-1647.
25.	Du Q, Zhang X, Cardinal J, et al. Wnt/beta-catenin signaling regulates cytokine-induced human inducible nitric oxide synthase expression by inhibiting nuclear factor-kappaB activation in cancer cells[J]. Cancer Res, 2009, 69(9):3764-3771.
26.	Franke TF. PI3K/Akt:getting it right matters[J]. Oncogene, 2008, 27(50):6473-6488.
27.	Villanueva A, Chiang DY, Newell P, et al. Pivotal role of mTOR signaling in hepatocellular carcinoma[J]. Gastroenterology, 2008, 135(6):1972-1983.
28.	Parekh P, Rao KV. Overexpression of cyclin D1 is associated with elevated levels of MAP kinases, Akt and Pak1 during diethylnitrosamine-induced progressive liver carcinogenesis[J]. Cell Biol Int, 2007, 31(1):35-43.
29.	Datta J, Majumder S, Kutay H, et al. Metallothionein expression is suppressed in primary human hepatocellular carcinomas and is mediated through inactivation of CCAAT/enhancer binding protein alpha by phosphatidylinositol 3-kinase signaling cascade[J]. Cancer Res, 2007, 67(6):2736-2746.
30.	Frau M, Ladu S, Calvisi DF, et al. Mybl2 expression is under genetic control and contributes to determine a hepatocellular carcinoma susceptible phenotype[J]. J Hepatol, 2011, 55(1):111-119.
31.	Dodge ME, Lum L. Drugging the cancer stem cell compartment: lessons learned from the hedgehog and Wnt signal transduction pathways[J]. Annu Rev Pharmacol Toxicol, 2011, 51:289-310.
32.	Neth P, Ries C, Karow M, et al. The Wnt signal transduction pathway in stem cells and cancer cells:influence on cellular invasion[J]. Stem Cell Rev, 2007, 3(1):18-29.
33.	You L, Kim J, He B, et al. Wnt-1 signal as a potential cancer therapeutic target[J]. Drug News Perspect, 2006, 19(1):27-31.
34.	Rao TP, Kühl M. An updated overview on Wnt signaling pathways:a prelude for more[J]. Circ Res, 2010, 106(12):1798-1806.
35.	Kaldis P, Pagano M. Wnt signaling in mitosis[J]. Dev Cell, 2009, 17(6):749-750.
36.	Taketo MM. Shutting down Wnt signal-activated cancer[J]. Nat Genet, 2004, 36(4):320-322.
37.	Guo Q, Shen S, Liao M, et al. NGX6 inhibits cell invasion and adhesion through suppression of Wnt/beta-catenin signal pathway in colon cancer[J]. Acta Biochim Biophys Sin (Shanghai), 42(7):450-456.
38.	Yuan F, Zhou W, Zou C, et al. Expression of Oct4 in HCC and modulation to wnt/β-catenin and TGF-βsignal pathways[J]. Mol Cell Biochem, 2010, 343(1-2):155-162.
39.	Ceballos MP, Parody JP, Alvarez Mde L, et al. Interferonalpha2b and transforming growth factor-beta1 treatments on HCC cell lines:Are Wnt/beta-catenin pathway and Smads signaling connected in hepatocellular carcinoma?[J]. Biochem Pharmacol, 2011, 82(11):1682-1691.
40.	Yun K, Im SH. Lef1 regulates COX-2 transcription in chondrocytes[J]. Biochem Biophys Res Commun, 2007, 364(2):270-275.
41.	Lee SH, Kim MH, Han HJ. Arachidonic acid potentiates hypoxiainduced VEGF expression in mouse embryonic stem cells:involvement of Notch, Wnt, and HIF-1alpha[J]. Am J Physiol Cell Physiol, 2009, 297(1):C207-C216.
42.	Wang LJ, Bai L, Su D, et al. Proinflammatory conditions promote hepatocellular carcinoma onset and progression via activation of Wnt and EGFR signaling pathways[J]. Mol Cell Biochem, 2013, 381(1-2):173-181.
43.	Yoshikawa R, Nakano Y, Tao L, et al. Hedgehog signal activation in oesophageal cancer patients undergoing neoadjuvant chemoradiotherapy[J]. Br J Cancer, 2008, 98(10):1670-1674.
44.	Hu WG, Liu T, Xiong JX, et al. Blockade of sonic hedgehog signal pathway enhances antiproliferative effect of EGFR inhibitor in pancreatic cancer cells[J]. Acta Pharmacol Sin, 2007, 28(8): 1224-1230.
45.	Riobo NA, Lu K, Emerson CP Jr. Hedgehog signal transduction: signal integration and cross talk in development and cancer[J]. Cell Cycle, 2006, 5(15):1612-1615.
46.	Fukaya M, Isohata N, Ohta H, et al. Hedgehog signal activation in gastric pit cell and in diffuse-type gastric cancer[J]. Gastroenterology, 2006, 131(1):14-29.

1. Lai EC, Tang CN, Yang GP, et al. Minimally invasive surgical treatment of hepatocellular carcinoma:long-term outcome[J]. World J Surg, 2009, 33(10):2150-2154.
2. Kim Y, Kim J, Lee HD, et al. Spectrum of EGFR gene copy number changes and KRAS gene mutation status in Korean triple negative breast cancer patients[J]. PLoS One, 2013, 8(10): e79014.
3. Glaysher S, Bolton LM, Johnson P, et al. Targeting EGFR and PI3K pathways in ovarian cancer[J]. Br J Cancer, 2013, 109(7):1786-1794.
4. Walker F, Abramowitz L, Benabderrahmane D, et al. Growth factor receptor expression in anal squamous lesions:modifications associated with oncogenic human papillomavirus and human immunodeficiency virus[J]. Hum Pathol, 2009, 40(11):1517-1527.
5. Jiang L, Huang J, Morehouse C, et al. Low frequency KRAS mutations in colorectal cancer patients and the presence of multiple mutations in oncogenic drivers in non-small cell lung cancer patients[J]. Cancer Genet, 2013, 206(9-10):330-339.
6. Oh HS, Eom DW, Kang GH, et al. Prognostic implications of EGFR and HER-2 alteration assessed by immunohistochemistry and silver in situ hybridization in gastric cancer patients following curative resection[J]. Gastric Cancer, 2013 Aug 17.[Epub ahead of print].
7. Narayanan R, Kim HN, Narayanan NK, et al. Epidermal growth factor-stimulated human cervical cancer cell growth is associated with EGFR and cyclin D1 activation, independent of COX-2 expression levels[J]. Int J Oncol, 2012, 40(1):13-20.
8. Yoshioka S, Takemasa I, Nagano H, et al. Molecular prediction of early recurrence after resection of hepatocellular carcinoma[J]. Eur J Cancer, 2009, 45(5):881-889.
9. Farber E, Sarma DS. Hepatocarcinogenesis:a dynamic cellular perspective[J]. Lab Invest, 1987, 56(1):4-22.
10. Farazi PA, DePinho RA. Hepatocellular carcinoma pathogenesis: from genes to environment[J]. Nat Rev Cancer, 2006, 6(9): 674-687.
11. Calvisi DF, Ladu S, Gorden A, et al. Mechanistic and prognostic significance of aberrant methylation in the molecular pathogenesis of human hepatocellular carcinoma[J]. J Clin Invest, 2007, 117(9):2713-2722.
12. Pearson G, Robinson F, Beers Gibson T, et al. Mitogen-activated protein (MAP) kinase pathways:regulation and physiological functions[J]. Endocr Rev, 2001, 22(2):153-183.
13. Sun X, Han L, Seth P, et al. Disordered purinergic signaling and abnormal cellular metabolism are associated with development of liver cancer in Cd39/ENTPD1 null mice[J]. Hepatology, 2013, 57(1):205-216.
14. Kaposi-Novak P, Lee JS, Gòmez-Quiroz L, et al. Met-regulated expression signature defines a subset of human hepatocellular carcinomas with poor prognosis and aggressive phenotype[J]. J Clin Invest, 2006, 116(6):1582-1595.
15. Cariani E, Lasserre C, Seurin D, et al. Differential expression of insulin-like growth factor II mRNA in human primary liver cancers, benign liver tumors, and liver cirrhosis[J]. Cancer Res, 1988, 48(23):6844-6849.
16. Baba M, Yamamoto R, Iishi H, et al. Ha-ras mutations in N-nitrosomorpholine-induced lesions and inhibition of hepatocarcinogenesis by antisense sequences in rat liver[J]. Int J Cancer, 1997, 72(5):815-820.
17. Calvisi DF, Pinna F, Pellegrino R, et al. Ras-driven proliferation and apoptosis signaling during rat liver carcinogenesis is under genetic control[J]. Int J Cancer, 2008, 123(9):2057-2064.
18. Weihrauch M, Benicke M, Lehnert G, et al. Frequent k-ras-2 mutations and p16(INK4A) methylation in hepatocellular carcinomas in workers exposed to vinyl chloride[J]. Br J Cancer, 2001, 84(7):982-989.
19. Lin YW, Yang JL. Cooperation of ERK and SCFSkp2 for MKP-1 destruction provides a positive feedback regulation of proliferating signaling[J]. J Biol Chem, 2006, 281(2):915-926.
20. Frau M, Feo F, Pascale RM. Pleiotropic effects of methionine adenosyltransferases deregulation as determinants of liver cancer progression and prognosis[J]. J Hepatol, 2013, 59(4):830-841.
21. Calvisi DF, Pinna F, Ladu S, et al. Forkhead box M1B is a determinant of rat susceptibility to hepatocarcinogenesis and sustains ERK activity in human HCC[J]. Gut, 2009, 58(5):679-687.
22. Calvisi DF, Pinna F, Meloni F, et al. Dual-specificity phosphatase 1 ubiquitination in extracellular signal-regulated kinase-mediated control of growth in human hepatocellular carcinoma[J]. Cancer Res, 2008, 68(11):4192-4200.
23. Fantappiè O, Masini E, Sardi I, et al. The MDR phenotype is associated with the expression of COX-2 and iNOS in a human hepatocellular carcinoma cell line[J]. Hepatology, 2002, 35(4): 843-852.
24. Calvisi DF, Pinna F, Ladu S, et al. Aberrant iNOS signaling is under genetic control in rodent liver cancer and potentially prognostic for the human disease[J]. Carcinogenesis, 2008, 29(8): 1639-1647.
25. Du Q, Zhang X, Cardinal J, et al. Wnt/beta-catenin signaling regulates cytokine-induced human inducible nitric oxide synthase expression by inhibiting nuclear factor-kappaB activation in cancer cells[J]. Cancer Res, 2009, 69(9):3764-3771.
26. Franke TF. PI3K/Akt:getting it right matters[J]. Oncogene, 2008, 27(50):6473-6488.
27. Villanueva A, Chiang DY, Newell P, et al. Pivotal role of mTOR signaling in hepatocellular carcinoma[J]. Gastroenterology, 2008, 135(6):1972-1983.
28. Parekh P, Rao KV. Overexpression of cyclin D1 is associated with elevated levels of MAP kinases, Akt and Pak1 during diethylnitrosamine-induced progressive liver carcinogenesis[J]. Cell Biol Int, 2007, 31(1):35-43.
29. Datta J, Majumder S, Kutay H, et al. Metallothionein expression is suppressed in primary human hepatocellular carcinomas and is mediated through inactivation of CCAAT/enhancer binding protein alpha by phosphatidylinositol 3-kinase signaling cascade[J]. Cancer Res, 2007, 67(6):2736-2746.
30. Frau M, Ladu S, Calvisi DF, et al. Mybl2 expression is under genetic control and contributes to determine a hepatocellular carcinoma susceptible phenotype[J]. J Hepatol, 2011, 55(1):111-119.
31. Dodge ME, Lum L. Drugging the cancer stem cell compartment: lessons learned from the hedgehog and Wnt signal transduction pathways[J]. Annu Rev Pharmacol Toxicol, 2011, 51:289-310.
32. Neth P, Ries C, Karow M, et al. The Wnt signal transduction pathway in stem cells and cancer cells:influence on cellular invasion[J]. Stem Cell Rev, 2007, 3(1):18-29.
33. You L, Kim J, He B, et al. Wnt-1 signal as a potential cancer therapeutic target[J]. Drug News Perspect, 2006, 19(1):27-31.
34. Rao TP, Kühl M. An updated overview on Wnt signaling pathways:a prelude for more[J]. Circ Res, 2010, 106(12):1798-1806.
35. Kaldis P, Pagano M. Wnt signaling in mitosis[J]. Dev Cell, 2009, 17(6):749-750.
36. Taketo MM. Shutting down Wnt signal-activated cancer[J]. Nat Genet, 2004, 36(4):320-322.
37. Guo Q, Shen S, Liao M, et al. NGX6 inhibits cell invasion and adhesion through suppression of Wnt/beta-catenin signal pathway in colon cancer[J]. Acta Biochim Biophys Sin (Shanghai), 42(7):450-456.
38. Yuan F, Zhou W, Zou C, et al. Expression of Oct4 in HCC and modulation to wnt/β-catenin and TGF-βsignal pathways[J]. Mol Cell Biochem, 2010, 343(1-2):155-162.
39. Ceballos MP, Parody JP, Alvarez Mde L, et al. Interferonalpha2b and transforming growth factor-beta1 treatments on HCC cell lines:Are Wnt/beta-catenin pathway and Smads signaling connected in hepatocellular carcinoma?[J]. Biochem Pharmacol, 2011, 82(11):1682-1691.
40. Yun K, Im SH. Lef1 regulates COX-2 transcription in chondrocytes[J]. Biochem Biophys Res Commun, 2007, 364(2):270-275.
41. Lee SH, Kim MH, Han HJ. Arachidonic acid potentiates hypoxiainduced VEGF expression in mouse embryonic stem cells:involvement of Notch, Wnt, and HIF-1alpha[J]. Am J Physiol Cell Physiol, 2009, 297(1):C207-C216.
42. Wang LJ, Bai L, Su D, et al. Proinflammatory conditions promote hepatocellular carcinoma onset and progression via activation of Wnt and EGFR signaling pathways[J]. Mol Cell Biochem, 2013, 381(1-2):173-181.
43. Yoshikawa R, Nakano Y, Tao L, et al. Hedgehog signal activation in oesophageal cancer patients undergoing neoadjuvant chemoradiotherapy[J]. Br J Cancer, 2008, 98(10):1670-1674.
44. Hu WG, Liu T, Xiong JX, et al. Blockade of sonic hedgehog signal pathway enhances antiproliferative effect of EGFR inhibitor in pancreatic cancer cells[J]. Acta Pharmacol Sin, 2007, 28(8): 1224-1230.
45. Riobo NA, Lu K, Emerson CP Jr. Hedgehog signal transduction: signal integration and cross talk in development and cancer[J]. Cell Cycle, 2006, 5(15):1612-1615.
46. Fukaya M, Isohata N, Ohta H, et al. Hedgehog signal activation in gastric pit cell and in diffuse-type gastric cancer[J]. Gastroenterology, 2006, 131(1):14-29.

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Effects of Signaling Pathway on Development of Hepatocellular Carcinoma

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