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Role of mTORC1 in intestinal epithelial repair and tumorigenesis

  • Harleen Kaur
  • Régis MoreauEmail author
Review
  • 123 Downloads

Abstract

mTORC1 signaling is the prototypical pathway regulating protein synthesis and cell proliferation. mTORC1 is active in stem cells located at the base of intestinal crypts but silenced as transit-amplifying cells differentiate into enterocytes or secretory cells along the epithelium. After an insult or injury, self-limiting and controlled activation of mTORC1 is critical for the renewal and repair of intestinal epithelium. mTORC1 promotes epithelial cell renewal by driving cryptic stem cell division, and epithelial cell repair by supporting the dedifferentiation and proliferation of enterocytes or secretory cells. Under repeated insult or injury, mTORC1 becomes constitutively active, triggering an irreversible return to stemness, cell division, proliferation, and inflammation among dedifferentiated epithelial cells. Epithelium-derived cytokines promulgate inflammation within the lamina propria, which in turn releases inflammatory factors that act back on the epithelium where undamaged intestinal epithelial cells participate in the pervading state of inflammation and become susceptible to tumorigenesis.

Graphical abstract

Keywords

Cell proliferation Stem cell Pro-inflammatory cytokines Immunity Colorectal cancer 

Abbreviations

AKT

Protein kinase B (PKB)

AMPK

AMP-activated protein kinase

ATG16L1

Autophagy related gene16L1

ATP

Adenosine triphosphate

BMP4

Bone morphogenetic protein 4

CA2

Carbonic anhydrase 2

CDK

Cyclin dependent kinases

CDX2

Homeobox protein CDX2

CKI

Casein kinase I

COX2

Cyclooxygenase

DLL

Delta like canonical notch ligand

eEF2

Eukaryotic elongation factor 2

eEF2K

Eukaryotic elongation factor 2 kinase

eIF-4e

Eukaryotic translation initiation factor 4E

EGF

Epidermal growth factor

ERK

Extracellular signal regulated kinase

EPHB2

Ephrin type-B receptor 2

FAK

Focal adhesion kinase

GATA

GATA binding protein

G-CSF

Granulocyte-colony stimulating factor

GSK3

Glycogen synthase kinase 3

hATH1 and mATH1

Human and mouse atonal homolog 1

HES1

Hairy/enhancer of split 1

HEY1

Hairy/enhancer-of-split related with YRPW mortif 1

IFNγ

Interferon γ

IGF-1

Insulin growth factor 1

IkBα

Inhibitor of kappa B

IKK

IkBα kinase

IRAK1

Interleukin-1 receptor associated kinase

IRS

Insulin receptor substrate

JAK

Janus kinase

JNK

c-Jun N-terminal kinases

KRAS

Kirsten rat sarcoma viral oncogene homolog

LEF1

Lymphoid enhancer binding factor 1

LRP5/6

Low density lipoprotein receptor-related protein 5/6

MEK

Mitogen activated protein/extracellular signal regulated kinase kinase

MUC

Mucin

MMP

Matrix metalloproteinase

NECD

Notch extra-cellular domain

NFkB

Nuclear factor kappa B

NOD2

Nucleotide-binding oligomerization domain-containing protein 2

NLRP3

Nod-like receptor family pyrin domain containing 3

PAMP

Pathogen associated molecular pattern

PDK1

Phosphoinositide dependent kinase 1

PtdIns

Phosphatidylinositide

PI3K

Phosphoinositide 3-kinase

PTEN

Phosphatase and tensin homolog deleted on chromosome 10

RAC1

Ras-related C3 botulinum toxin substrate 1

REGγ

Regenerating gene gamma

RTK

Receptor tyrosine kinase

SIRT1

Sirtuin 1

SOCS3

Suppressor of cytokine signaling 3

STAT3

Signal transducer and activator of transcription 3

TAB

TAK1 binding proteins

TAK1

Transforming growth factor beta-activated kinase 1

TEAD

Transcription enhancer factor TEF-1

TCF

T cell factor transcription factor

TLR

Toll-like receptor

TM4SF4

Transmembrane 4 L six family member 4

TNFαR

Tumor necrosis α receptor

TRAF

TNFαR associated factor

Notes

Author contributions

HK conducted the literature search, drafted and revised the manuscript. RM critically reviewed and revised the manuscript.

Funding

Support was received from the Agriculture and Food Research Initiative (Award Number 2016-67017-24431) and from the USDA National Institute of Food and Agriculture (Program: Food Safety, Nutrition, and Health—A1341).

Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interest.

References

  1. 1.
    Ayabe T, Satchell DP, Wilson CL, Parks WC, Selsted ME, Ouellette AJ (2000) Secretion of microbicidal alpha-defensins by intestinal Paneth cells in response to bacteria. Nat Immunol 1:113–118CrossRefPubMedGoogle Scholar
  2. 2.
    Pelaseyed T, Bergstrom JH, Gustafsson JK, Ermund A, Birchenough GM, Schutte A et al (2014) The mucus and mucins of the goblet cells and enterocytes provide the first defense line of the gastrointestinal tract and interact with the immune system. Immunol Rev 260:8–20CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Van Der Flier LG, Clevers H (2009) Stem cells, self-renewal, and differentiation in the intestinal epithelium. Annu Rev Physiol 71:241–260CrossRefPubMedGoogle Scholar
  4. 4.
    Noah TK, Donahue B, Shroyer NF (2011) Intestinal development and differentiation. Exp Cell Res 317:2702–2710CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Chakrabarti S, Liehl P, Buchon N, Lemaitre B (2012) Infection-induced host translational blockage inhibits immune responses and epithelial renewal in the Drosophila gut. Cell Host Microbe 12:60–70CrossRefPubMedGoogle Scholar
  6. 6.
    García-Arrarás JE, Valentín-Tirado G, Flores JE, Rosa RJ, Rivera-Cruz A, San Miguel-Ruiz JE et al (2011) Cell dedifferentiation and epithelial to mesenchymal transitions during intestinal regeneration in H. glaberrima. BMC Dev Biol 11:61CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Vidyasagar LY, Reshu G, Lauren V, Astrid G, Paul O, Sadasivan V (2016) An amino acid-based oral rehydration solution (AA-ORS) enhanced intestinal epithelial proliferation in mice exposed to radiation. Sci Rep 6:37220CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Yousefi M, Nakauka-Ddamba A, Berry CT, Li N, Schoenberger J, Simeonov KP et al (2018) Calorie restriction governs intestinal epithelial regeneration through cell-autonomous regulation of mTORC1 in reserve stem cells. Stem Cell Rep 10:703–711CrossRefGoogle Scholar
  9. 9.
    Bauer C, Duewell P, Mayer C, Lehr HA, Fitzgerald KA, Dauer M et al (2010) Colitis induced in mice with dextran sulfate sodium (DSS) is mediated by the NLRP3 inflammasome. Gut 59:1192–1199CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Wilson GS, George J (2014) Physical and chemical insults induce inflammation and gastrointestinal cancers. Cancer Lett 345:190–195CrossRefPubMedGoogle Scholar
  11. 11.
    Yi G, Li L, Luo M, He X, Zou Z, Gu Z et al (2017) Heat stress induces intestinal injury through lysosome-and mitochondria-dependent pathway in vivo and in vitro. Oncotarget 8:40741–40755PubMedPubMedCentralGoogle Scholar
  12. 12.
    Costa R, Snipe R, Kitic C, Gibson P (2017) Systematic review: exercise-induced gastrointestinal syndrome—implications for health and intestinal disease. Aliment Pharmacol Ther 46:246–265CrossRefPubMedGoogle Scholar
  13. 13.
    Elamin E, Jonkers D, Juuti-Uusitalo K, van IJzendoorn S, Troost F, Duimel H et al (2012) Effects of ethanol and acetaldehyde on tight junction integrity: in vitro study in a three dimensional intestinal epithelial cell culture model. PLoS One 7:e35008CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Li L, Chan R, Lu L, Shen J, Zhang L, Wu W et al (2014) Cigarette smoking and gastrointestinal diseases: the causal relationship and underlying molecular mechanisms. Int J Mol Med 34:372–380CrossRefPubMedGoogle Scholar
  15. 15.
    Maiden L, Thjodleifsson B, Seigal A, Bjarnason II, Scott D, Birgisson S et al (2007) Long-term effects of nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 selective agents on the small bowel: a cross-sectional capsule enteroscopy study. Clin Gastroenterol Hepatol 5:1040–1045CrossRefPubMedGoogle Scholar
  16. 16.
    Rosenfeld CS (2017) Gut dysbiosis in animals due to environmental chemical exposures. Front Cell Infect Microbiol 7:396CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Earley ZM, Akhtar S, Green SJ, Naqib A, Khan O, Cannon AR et al (2015) Burn injury alters the intestinal microbiome and increases gut permeability and bacterial translocation. PLoS One 10:e0129996CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Qin Q, Xu X, Wang X, Wu H, Zhu H, Hou Y et al (2018) Glutamate alleviates intestinal injury, maintains mTOR and suppresses TLR4 and NOD signaling pathways in weanling pigs challenged with lipopolysaccharide. Sci Rep 8:15124CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Ewaschuk JB, Murdoch GK, Johnson IR, Madsen KL, Field CJ (2011) Glutamine supplementation improves intestinal barrier function in a weaned piglet model of Escherichia coli infection. Br J Nutr 106:870–877CrossRefPubMedGoogle Scholar
  20. 20.
    Yi D, Hou Y, Wang L, Ouyang W, Long M, Zhao D et al (2015) l-Glutamine enhances enterocyte growth via activation of the mTOR signaling pathway independently of AMPK. Amino Acids 47:65–78CrossRefPubMedGoogle Scholar
  21. 21.
    Zhou W, Li W, Zheng X-H, Rong X, Huang L-G (2014) Glutamine downregulates TLR-2 and TLR-4 expression and protects intestinal tract in preterm neonatal rats with necrotizing enterocolitis. J Pediatr Surg 49:1057–1063CrossRefPubMedGoogle Scholar
  22. 22.
    Park J-H, Kotani T, Konno T, Setiawan J, Kitamura Y, Imada S et al (2016) Promotion of intestinal epithelial cell turnover by commensal bacteria: role of short-chain fatty acids. PLoS One 11:e0156334CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Karin M, Clevers H (2016) Reparative inflammation takes charge of tissue regeneration. Nature 529:307–315CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Dignass AU, Podolsky DK (1993) Cytokine modulation of intestinal epithelial cell restitution: central role of transforming growth factor β. Gastroenterology 105:1323–1332CrossRefPubMedGoogle Scholar
  25. 25.
    Sturm A, Dignass AU (2008) Epithelial restitution and wound healing in inflammatory bowel disease. World J Gastroenterol WJG 14:348–353CrossRefPubMedGoogle Scholar
  26. 26.
    Okamoto R, Watanabe M (2016) Role of epithelial cells in the pathogenesis and treatment of inflammatory bowel disease. J Gastroenterol 51:11–21CrossRefPubMedGoogle Scholar
  27. 27.
    Taniguchi K, Wu L-W, Grivennikov SI, De Jong PR, Lian I, Yu F-X et al (2015) A gp130–Src–YAP module links inflammation to epithelial regeneration. Nature 519:57–62CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Taniguchi K, Moroishi T, de Jong PR, Krawczyk M, Grebbin BM, Luo H et al (2017) YAP–IL-6ST autoregulatory loop activated on APC loss controls colonic tumorigenesis. Proc Natl Acad Sci 114:1643–1648CrossRefPubMedGoogle Scholar
  29. 29.
    Schwitalla S, Fingerle AA, Cammareri P, Nebelsiek T, Göktuna SI, Ziegler PK et al (2013) Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties. Cell 152:25–38CrossRefPubMedGoogle Scholar
  30. 30.
    Zhou Y, Rychahou P, Wang Q, Weiss HL, Evers BM (2015) TSC2/mTORC1 signaling controls Paneth and goblet cell differentiation in the intestinal epithelium. Cell Death Dis 6:e1631CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Gregorieff A, Liu Y, Inanlou MR, Khomchuk Y, Wrana JL (2015) Yap-dependent reprogramming of Lgr5+ stem cells drives intestinal regeneration and cancer. Nature 526:715–718CrossRefPubMedGoogle Scholar
  32. 32.
    Sansom OJ, Reed KR, Hayes AJ, Ireland H, Brinkmann H, Newton IP et al (2004) Loss of Apc in vivo immediately perturbs Wnt signaling, differentiation, and migration. Genes Dev 18:1385–1390CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Nakamura T, Tsuchiya K, Watanabe M (2007) Crosstalk between Wnt and Notch signaling in intestinal epithelial cell fate decision. J Gastroenterol 42:705–710CrossRefPubMedGoogle Scholar
  34. 34.
    Artavanis-Tsakonas SF, Mathilde H, Philippos M, Sylvie R, Daniel L (2005) Notch signals control the fate of immature progenitor cells in the intestine. Nature 435:964–968CrossRefPubMedGoogle Scholar
  35. 35.
    Faller WJ, Jackson TJ, Knight JR, Ridgway RA, Jamieson T, Karim SA et al (2015) mTORC1-mediated translational elongation limits intestinal tumour initiation and growth. Nature 517:497–500CrossRefPubMedGoogle Scholar
  36. 36.
    Kaur H, He B, Zhang C, Rodriguez E, Hage DS, Moreau R (2018) Piperine potentiates curcumin-mediated repression of mTORC1 signaling in human intestinal epithelial cells: implications for the inhibition of protein synthesis and TNFalpha signaling. J Nutr Biochem 57:276–286CrossRefPubMedGoogle Scholar
  37. 37.
    Aziz M, Ishihara S, Ansary MU, Sonoyama H, Tada Y, Oka A et al (2018) Crosstalk between TLR5 and Notch1 signaling in epithelial cells during intestinal inflammation. Int J Mol Med 32:1051–1062CrossRefGoogle Scholar
  38. 38.
    Kapuria S, Karpac J, Biteau B, Hwangbo D, Jasper H (2012) Notch-mediated suppression of TSC2 expression regulates cell differentiation in the Drosophila intestinal stem cell lineage. PLoS Genet 8:e1003045CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Fu Z, Kim J, Vidrich A, Sturgill TW, Cohn SM (2009) Intestinal cell kinase, a MAP kinase-related kinase, regulates proliferation and G1 cell cycle progression of intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol. 297:G632–G640CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Bray SJ (2006) Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol 7:678–689CrossRefPubMedGoogle Scholar
  41. 41.
    Grivennikov S, Karin E, Terzic J, Mucida D, Yu G-Y, Vallabhapurapu S et al (2009) IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell 15:103–113CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Guan Y, Zhang L, Li X, Zhang X, Liu S, Gao N et al (2015) Repression of mammalian target of rapamycin complex 1 inhibits intestinal regeneration in acute inflammatory bowel disease models. J Immunol (Baltimore, Md: 1950) 195:339–346CrossRefGoogle Scholar
  43. 43.
    Zhao B, Tumaneng K, Guan K-L (2011) The Hippo pathway in organ size control, tissue regeneration and stem cell self-renewal. Nat Cell Biol 13:877–883CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Deng F, Peng L, Li Z, Tan G, Liang E, Chen S et al (2018) YAP triggers the Wnt/β-catenin signalling pathway and promotes enterocyte self-renewal, regeneration and tumorigenesis after DSS-induced injury. Cell Death Dis 9:153CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Khor B, Gardet A, Xavier RJ (2011) Genetics and pathogenesis of inflammatory bowel disease. Nature 474:307–317CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Lin L, Liu A, Peng Z, Lin HJ, Li PK, Li C et al (2011) STAT3 is necessary for proliferation and survival in colon cancer-initiating cells. Cancer Res 71:7226–7237CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Villani AC, Lemire M, Fortin G, Louis E, Silverberg MS, Collette C et al (2009) Common variants in the NLRP3 region contribute to Crohn’s disease susceptibility. Nat Genet 41:71–76CrossRefPubMedGoogle Scholar
  48. 48.
    Cosin-Roger J, Simmen S, Melhem H, Atrott K, Frey-Wagner I, Hausmann M et al (2017) Hypoxia ameliorates intestinal inflammation through NLRP3/mTOR downregulation and autophagy activation. Nat Commun 8:98CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Lin X, Sun Q, Zhou L, He M, Dong X, Lai M et al (2018) Colonic epithelial mTORC1 promotes ulcerative colitis through COX-2-mediated Th17 responses. Mucosal Immunol 11:1663–1673CrossRefPubMedGoogle Scholar
  50. 50.
    Lyons J, Ghazi PC, Starchenko A, Tovaglieri A, Baldwin KR, Poulin EJ et al (2018) The colonic epithelium plays an active role in promoting colitis by shaping the tissue cytokine profile. PLoS Biol 16:e2002417CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Deng L, Zhou J-F, Sellers RS, Li J-F, Nguyen AV, Wang Y et al (2010) A novel mouse model of inflammatory bowel disease links mammalian target of rapamycin-dependent hyperproliferation of colonic epithelium to inflammation-associated tumorigenesis. Am J Pathol 176:952–967CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Kanneganti RK, Si Ming M, Malireddi RKS, Sannula K, Qifan Z, Amanda RB et al (2016) NLRC3 is an inhibitory sensor of PI3K–mTOR pathways in cancer. Nature 540:583CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Sampson LL, Davis AK, Grogg MW, Zheng Y (2015) mTOR disruption causes intestinal epithelial cell defects and intestinal atrophy postinjury in mice. FASEB J 30:1263–1275CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Barron L, Sun RC, Aladegbami B, Erwin CR, Warner BW, Guo J (2017) Intestinal epithelial-specific mTORC1 activation enhances intestinal adaptation after small bowel resection. Cell Mol Gastroenterol Hepatol 3:231–244CrossRefPubMedGoogle Scholar
  55. 55.
    Brandt M, Grazioso TP, Fawal MA, Tummala KS, Torres-Ruiz R, Rodriguez-Perales S et al (2018) mTORC1 inactivation promotes colitis-induced colorectal cancer but protects from APC loss-dependent tumorigenesis. Cell Metab 27(118–35):e8Google Scholar
  56. 56.
    Thiem S, Pierce TP, Palmieri M, Putoczki TL, Buchert M, Preaudet A et al (2013) mTORC1 inhibition restricts inflammation-associated gastrointestinal tumorigenesis in mice. J Clin Invest 123:767–781PubMedPubMedCentralGoogle Scholar
  57. 57.
    Suer S, Ampasala D, Walsh MF, Basson MD (2009) Role of ERK/mTOR signaling in TGFβ-modulated focal adhesion kinase mRNA stability and protein synthesis in cultured rat IEC-6 intestinal epithelial cells. Cell Tissue Res 336:213–223CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Owen KA, Abshire MY, Tilghman RW, Casanova JE, Bouton AH (2011) FAK regulates intestinal epithelial cell survival and proliferation during mucosal wound healing. PLoS One 6:e23123CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Walsh MF, Ampasala DR, Hatfield J, Vander Heide R, Suer S, Rishi AK et al (2008) Transforming growth factor-β stimulates intestinal epithelial focal adhesion kinase synthesis via Smad-and p38-dependent mechanisms. Am J Pathol 173:385–399CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Tan B, Xiao H, Xiong X, Wang J, Li G, Yin Y et al (2015) l-arginine improves DNA synthesis in LPS-challenged enterocytes. Front Biosci (Landmark ed) 20:989–1003CrossRefGoogle Scholar
  61. 61.
    Tan B, Yin Y, Kong X, Li P, Li X, Gao H et al (2010) l-Arginine stimulates proliferation and prevents endotoxin-induced death of intestinal cells. Amino Acids 38:1227–1235CrossRefPubMedGoogle Scholar
  62. 62.
    Bar-Peled L, Sabatini DM (2014) Regulation of mTORC1 by amino acids. Trends Cell Biol 24:400–406CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Sancak Y, Bar-Peled L, Zoncu R, Markhard AL, Nada S, Sabatini DM (2010) Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell 141:290–303CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Ban H, Shigemitsu K, Yamatsuji T, Haisa M, Nakajo T, Takaoka M et al (2004) Arginine and leucine regulate p70 S6 kinase and 4E-BP1 in intestinal epithelial cells. Int J Mol Med 13:537–543PubMedGoogle Scholar
  65. 65.
    Seidel E, Ragan V (1997) Inhibition by rapamycin of ornithine decarboxylase and epithelial cell proliferation in intestinal IEC-6 cells in culture. Br J Pharmacol 120:571–574CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Minois N, Carmona-Gutierrez D, Madeo F (2011) Polyamines in aging and disease. Aging (Albany NY) 3:716–732CrossRefGoogle Scholar
  67. 67.
    Timmons J, Chang ET, Wang J-Y, Rao JN (2012) Polyamines and gut mucosal homeostasis. J Gastrointest Digest Syst 2:001Google Scholar
  68. 68.
    Wu G, Flynn NE, Knabe DA (2000) Enhanced intestinal synthesis of polyamines from proline in cortisol-treated piglets. Am J Physiol Endocrinol Metab 279:E395–E402CrossRefPubMedGoogle Scholar
  69. 69.
    Wang J-Y, Johnson LR (1991) Polyamines and ornithine decarboxylase during repair of duodenal mucosa after stress in rats. Gastroenterology 100:333–343CrossRefPubMedGoogle Scholar
  70. 70.
    Feng Y, Demehri FR, Xiao W, Tsai Y-H, Jones JC, Brindley CD et al (2017) Interdependency of EGF and GLP-2 signaling in attenuating mucosal atrophy in a mouse model of parenteral nutrition. Cell Mol Gastroenterol Hepatol 3:447–468CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Brubaker PL, Izzo A, Hill M, Drucker DJ (1997) Intestinal function in mice with small bowel growth induced by glucagon-like peptide-2. Am J Physiol Endocrinol Metab 272:E1050–E1058CrossRefGoogle Scholar
  72. 72.
    Lee J, Koehler J, Yusta B, Bahrami J, Matthews D, Rafii M et al (2017) Enteroendocrine-derived glucagon-like peptide-2 controls intestinal amino acid transport. Mol Metab 6:245–255CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Mendoza MC, Er EE, Blenis J (2011) The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensation. Trends Biochem Sci 36:320–328CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Rossi O, van Baarlen P, Wells JM (2011) Host-recognition of pathogens and commensals in the mammalian intestine. Curr Top Microbiol Immunol 358:291–321Google Scholar
  75. 75.
    Yang Y, Li W, Sun Y, Han F, Hu C-AA, Wu Z (2015) Amino acid deprivation disrupts barrier function and induces protective autophagy in intestinal porcine epithelial cells. Amino acids 47:2177–2184CrossRefPubMedGoogle Scholar
  76. 76.
    Nowacki M (1993) Cell proliferation in colonic crypts of germ-free and conventional mice—preliminary report. Folia Histochem Cytobiol 31:77–81PubMedGoogle Scholar
  77. 77.
    Alam M, Midtvedt T, Uribe A (1994) Differential cell kinetics in the ileum and colon of germfree rats. Scand J Gastroenterol 29:445–451CrossRefPubMedGoogle Scholar
  78. 78.
    Peck BC, Mah AT, Pitman WA, Ding S, Lund PK, Sethupathy P (2017) Functional transcriptomics in diverse intestinal epithelial cell types reveals robust microRNA sensitivity in intestinal stem cells to microbial status. J Biol Chem 292:2586–2600 (jbc. M116. 770099) CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Hooper LV, Gordon JI (2001) Commensal host–bacterial relationships in the gut. Science 292:1115–1118CrossRefPubMedGoogle Scholar
  80. 80.
    Smith K, McCoy KD, Macpherson AJ (2007) Use of axenic animals in studying the adaptation of mammals to their commensal intestinal microbiota. Semin Immunol 19:59–69CrossRefPubMedGoogle Scholar
  81. 81.
    Khoury KA, Floch MH, Hersh T (1969) Small intestinal mucosal cell proliferation and bacterial flora in the conventionalization of the germfree mouse. J Exp Med 130:659–670CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Kaiko GE, Ryu SH, Koues OI, Collins PL, Solnica-Krezel L, Pearce EJ et al (2016) The colonic crypt protects stem cells from microbiota-derived metabolites. Cell 165:1708–1720CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Zhang J, Yi M, Zha L, Chen S, Li Z, Li C et al (2016) Sodium butyrate induces endoplasmic reticulum stress and autophagy in colorectal cells: implications for apoptosis. PLoS One 11:e0147218CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Tang Y, Chen Y, Jiang H, Nie D (2011) Short-chain fatty acids induced autophagy serves as an adaptive strategy for retarding mitochondria-mediated apoptotic cell death. Cell Death Differ 18:602–618CrossRefPubMedGoogle Scholar
  85. 85.
    Martini E, Krug SM, Siegmund B, Neurath MF, Becker C (2017) Mend your fences: the epithelial barrier and its relationship with mucosal immunity in inflammatory bowel disease. Cell Mol Gastroenterol Hepatol 4:33–46CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Zhao Y, Chen F, Wu W, Sun M, Bilotta AJ, Yao S et al (2018) GPR43 mediates microbiota metabolite SCFA regulation of antimicrobial peptide expression in intestinal epithelial cells via activation of mTOR and STAT3. Mucosal Immunol 11:752–762CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    He Z, He X, Chen Z, Ke J, He X, Yuan R et al (2014) Activation of the mTORC1 and STAT3 pathways promotes the malignant transformation of colitis in mice. Oncol Rep 32:1873–1880CrossRefPubMedGoogle Scholar
  88. 88.
    Ro S-H, Xue X, Ramakrishnan SK, Cho C-S, Namkoong S, Jang I et al (2016) Tumor suppressive role of sestrin2 during colitis and colon carcinogenesis. Elife 5:e12204CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Krah NM, Murtaugh LC (2016) Differentiation and inflammation:‘Best Enemies’ in gastrointestinal carcinogenesis. Trends Cancer 2:723–735CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Jilkine A, Gutenkunst RN (2014) Effect of dedifferentiation on time to mutation acquisition in stem cell-driven cancers. PLoS Comput Biol 10:e1003481CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Mills JC, Sansom OJ (2015) Reserve stem cells: differentiated cells reprogram to fuel repair, metaplasia, and neoplasia in the adult gastrointestinal tract. Sci Signal 8:re8CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Sugao Y, Yao T, Kubo C, Tsuneyoshi M (1997) Improved prognosis of solid-type poorly differentiated colorectal adenocarcinoma: a clinicopathological and immunohistochemical study. Histopathology 31:123–133CrossRefPubMedGoogle Scholar
  93. 93.
    Scholer-Dahirel A, Schlabach MR, Loo A, Bagdasarian L, Meyer R, Guo R et al (2011) Maintenance of adenomatous polyposis coli (APC)-mutant colorectal cancer is dependent on Wnt/β-catenin signaling. Proc Natl Acad Sci USA 108:17135–17140CrossRefPubMedGoogle Scholar
  94. 94.
    Hu H, Zhang H, Ge W, Liu X, Loera S, Chu P et al (2012) Secreted protein acidic and rich in cysteines-like 1 suppresses aggressiveness and predicts better survival in colorectal cancers. Clin Cancer Res 18:5438–5448CrossRefPubMedGoogle Scholar
  95. 95.
    Hatano Y, Semi K, Hashimoto K, Lee MS, Hirata A, Tomita H et al (2015) Reducing DNA methylation suppresses colon carcinogenesis by inducing tumor cell differentiation. Carcinogenesis 36:719–729CrossRefPubMedGoogle Scholar
  96. 96.
    Yang B, Cao L, Liu B, McCaig CD, Pu J (2013) The transition from proliferation to differentiation in colorectal cancer is regulated by the calcium activated chloride channel A1. PLoS One 8:e60861CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Fujishita T, Aoki K, Lane HA, Aoki M, Taketo MM (2008) Inhibition of the mTORC1 pathway suppresses intestinal polyp formation and reduces mortality in ApcΔ716 mice. Proc Natl Acad Sci 105:13544–13549CrossRefPubMedGoogle Scholar
  98. 98.
    Valvezan AJ, Huang J, Lengner CJ, Pack M, Klein PS (2014) Oncogenic mutations in adenomatous polyposis coli (Apc) activate mechanistic target of rapamycin complex 1 (mTORC1) in mice and zebrafish. Dis Models Mech 7:63–71CrossRefGoogle Scholar
  99. 99.
    Zhang W, Ding M-L, Zhang J-N, Qiu J-R, Shen Y-H, Ding X-Y et al (2015) mTORC1 maintains the tumorigenicity of SSEA-4 + high-grade osteosarcoma. Sci Rep 5:9604CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Dow LE, O’Rourke KP, Simon J, Tschaharganeh DF, van Es JH, Clevers H et al (2015) Apc restoration promotes cellular differentiation and reestablishes crypt homeostasis in colorectal cancer. Cell 161:1539–1552CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Schneikert J, Behrens J (2007) The canonical Wnt signalling pathway and its APC partner in colon cancer development. Gut 56:417–425CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Andreu P, Colnot S, Godard C, Gad S, Chafey P, Niwa-Kawakita M et al (2005) Crypt-restricted proliferation and commitment to the Paneth cell lineage following Apc loss in the mouse intestine. Development 132:1443–1451CrossRefPubMedGoogle Scholar
  103. 103.
    Zhou Y, Rychahou P, Wang Q, Weiss HL, Evers BM (2015) TSC2/mTORC1 signaling controls Paneth and goblet cell differentiation in the intestinal epithelium. Cell Death Dis 6:e1631CrossRefPubMedPubMedCentralGoogle Scholar
  104. 104.
    Zhou Y, Wang Q, Guo Z, Weiss HL, Evers BM (2012) Nuclear factor of activated T-cell c3 inhibition of mammalian target of rapamycin signaling through induction of regulated in development and DNA damage response 1 in human intestinal cells. Mol Biol Cell 23:2963–2972CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Hsu H-P, Lai M-D, Lee J-C, Yen M-C, Weng T-Y, Chen W-C et al (2017) Mucin 2 silencing promotes colon cancer metastasis through interleukin-6 signaling. Sci Rep 7:5823CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    Gavert N, Ben-Ze’ev A (2008) Epithelial–mesenchymal transition and the invasive potential of tumors. Trends Mol Med 14:199–209CrossRefPubMedGoogle Scholar
  107. 107.
    Friedmann-Morvinski D, Verma IM (2014) Dedifferentiation and reprogramming: origins of cancer stem cells. EMBO Rep 15:244–253CrossRefPubMedPubMedCentralGoogle Scholar
  108. 108.
    Karvellas CJ, Fedorak RN, Hanson J, Wong CK (2007) Increased risk of colorectal cancer in ulcerative colitis patients diagnosed after 40 years of age. Can J Gastroenterol Hepatol 21:443–446Google Scholar
  109. 109.
    Tsianos EV (2000) Risk of cancer in inflammatory bowel disease (IBD). Eur J Intern Med 11:75–78CrossRefPubMedGoogle Scholar
  110. 110.
    Hergovich A, Stegert MR, Schmitz D, Hemmings BA (2006) NDR kinases regulate essential cell processes from yeast to humans. Nat Rev Mol Cell Biol 7:253–264CrossRefPubMedGoogle Scholar
  111. 111.
    Cai J, Zhang N, Zheng Y, De Wilde RF, Maitra A, Pan D (2010) The Hippo signaling pathway restricts the oncogenic potential of an intestinal regeneration program. Genes Dev 24:2383–2388CrossRefPubMedPubMedCentralGoogle Scholar
  112. 112.
    Camargo FD, Gokhale S, Johnnidis JB, Fu D, Bell GW, Jaenisch R et al (2007) YAP1 increases organ size and expands undifferentiated progenitor cells. Curr Biol 17:2054–2060CrossRefPubMedPubMedCentralGoogle Scholar
  113. 113.
    Tumaneng K, Schlegelmilch K, Russell R, Yimlamai D, Basnet H, Mahadevan N et al (2012) YAP mediates crosstalk between the Hippo and PI3K-TOR pathways by suppressing PTEN via miR-29. Nat Cell Biol 14:1322–1329CrossRefPubMedPubMedCentralGoogle Scholar
  114. 114.
    Straßburger K, Tiebe M, Pinna F, Breuhahn K, Teleman AA (2012) Insulin/IGF signaling drives cell proliferation in part via Yorkie/YAP. Dev Biol 367:187–196CrossRefPubMedGoogle Scholar
  115. 115.
    Park YY, Sohn BH, Johnson RL, Kang MH, Kim SB, Shim JJ et al (2016) YAP1 and TAZ Activates mTORC1 pathway by regulating amino acid transporters in hepatocellular carcinoma. Hepatology 63:159–172CrossRefPubMedGoogle Scholar
  116. 116.
    Liang N, Zhang C, Dill P, Panasyuk G, Pion D, Koka V et al (2014) Regulation of YAP by mTOR and autophagy reveals a therapeutic target of tuberous sclerosis complex. J Exp Med 211:2249–2263CrossRefPubMedPubMedCentralGoogle Scholar
  117. 117.
    Kim H-B, Kim M, Park Y-S, Park I, Kim T, Yang S-Y et al (2017) Prostaglandin E2 activates YAP and a positive-signaling loop to promote colon regeneration after colitis but also carcinogenesis in mice. Gastroenterology 152:616–630CrossRefPubMedGoogle Scholar
  118. 118.
    Yu M, Luo Y, Cong Z, Mu Y, Qiu Y, Zhong M (2018) MicroRNA-590-5p inhibits intestinal inflammation by targeting YAP. J Crohns Colitis 12:993–1004CrossRefPubMedGoogle Scholar
  119. 119.
    Yao F, Zhou W, Zhong C, Fang W (2015) LATS2 inhibits the activity of NF-κ B signaling by disrupting the interaction between TAK1 and IKKβ. Tumor Biol 36:7873–7879CrossRefGoogle Scholar
  120. 120.
    Wang Q, Gao X, Yu T, Yuan L, Dai J, Wang W et al (2018) REGγ controls Hippo signaling and reciprocal NF-κB–YAP regulation to promote colon cancer. Clin Cancer Res 24:2015–2025CrossRefPubMedGoogle Scholar
  121. 121.
    Jenkins BJ, Grail D, Nheu T, Najdovska M, Wang B, Waring P et al (2005) Hyperactivation of Stat3 in gp130 mutant mice promotes gastric hyperproliferation and desensitizes TGF-beta signaling. Nat Med 11:845–852CrossRefPubMedGoogle Scholar
  122. 122.
    Huang YJ, Yang CK, Wei PL, Huynh T-T, Whang-Peng J, Meng T-C et al (2017) Ovatodiolide suppresses colon tumorigenesis and prevents polarization of M2 tumor-associated macrophages through YAP oncogenic pathways. J Hematol Oncol 10:60CrossRefPubMedPubMedCentralGoogle Scholar
  123. 123.
    Ou C, Sun Z, Li X, Ren W, Qin Z, Zhang X et al (2017) MiR-590-5p, a density-sensitive microRNA, inhibits tumorigenesis by targeting YAP1 in colorectal cancer. Cancer Lett 399:53–63CrossRefPubMedPubMedCentralGoogle Scholar
  124. 124.
    Zhang G-J, San Y-Z, Zhang H-Q, Zhang J-F, Yang Z, Yu Z-F et al (2017) MiR-590-5p as potential oncogenic microRNA of human colorectal cancer cells by targeting PTEN. Int J Clin Exp Pathol 10:1322–1330Google Scholar
  125. 125.
    Meng RD, Shelton CC, Li Y-M, Qin L-X, Notterman D, Paty PB et al (2009) γ-Secretase inhibitors abrogate oxaliplatin-induced activation of the Notch-1 signaling pathway in colon cancer cells resulting in enhanced chemosensitivity. Can Res 69:573–582CrossRefGoogle Scholar
  126. 126.
    Zhang X, Chen T, Zhang J, Mao Q, Li S, Xiong W et al (2012) Notch1 promotes glioma cell migration and invasion by stimulating β-catenin and NF-κB signaling via AKT activation. Cancer Sci 103:181–190CrossRefPubMedGoogle Scholar
  127. 127.
    Koduru S, Kumar R, Srinivasan S, Evers MB, Damodaran C (2010) Notch-1 inhibition by Withaferin-A: a therapeutic target against colon carcinogenesis. Mol Cancer Ther 9:202–210CrossRefPubMedPubMedCentralGoogle Scholar
  128. 128.
    Shinoda M, Shin-Ya M, Naito Y, Kishida T, Ito R, Suzuki N et al (2010) Early-stage blocking of Notch signaling inhibits the depletion of goblet cells in dextran sodium sulfate-induced colitis in mice. J Gastroenterol 45:608–617CrossRefPubMedGoogle Scholar
  129. 129.
    Zheng X, Tsuchiya K, Okamoto R, Iwasaki M, Kano Y, Sakamoto N et al (2011) Suppression of hath1 gene expression directly regulated by hes1 via notch signaling is associated with goblet cell depletion in ulcerative colitis. Inflamm Bowel Dis 17:2251–2260CrossRefPubMedGoogle Scholar
  130. 130.
    Gersemann M, Becker S, Kübler I, Koslowski M, Wang G, Herrlinger KR et al (2009) Differences in goblet cell differentiation between Crohn’s disease and ulcerative colitis. Differentiation 77:84–94CrossRefPubMedGoogle Scholar
  131. 131.
    Francipane MG, Lagasse E (2013) Selective targeting of human colon cancer stem-like cells by the mTOR inhibitor Torin-1. Oncotarget 4:1948–1962CrossRefPubMedPubMedCentralGoogle Scholar
  132. 132.
    Suliman MA, Zhang Z, Na H, Ribeiro AL, Zhang Y, Niang B et al (2016) Niclosamide inhibits colon cancer progression through downregulation of the Notch pathway and upregulation of the tumor suppressor miR-200 family. Int J Mol Med 38:776–784CrossRefPubMedPubMedCentralGoogle Scholar
  133. 133.
    Dahan S, Rabinowitz KM, Martin AP, Berin MC, Unkeless JC, Mayer L (2011) Notch-1 signaling regulates intestinal epithelial barrier function, through interaction with CD4 + T cells, in mice and humans. Gastroenterology 140:550–559CrossRefPubMedGoogle Scholar
  134. 134.
    Garg P, Jeppsson S, Dalmasso G, Ghaleb AM, McConnell BB, Yang VW et al (2011) Notch1 regulates the effects of matrix metalloproteinase-9 on colitis-associated cancer in mice. Gastroenterology 141:1381–1392CrossRefPubMedPubMedCentralGoogle Scholar
  135. 135.
    Pope JL, Bhat AA, Sharma A, Ahmad R, Krishnan M, Washington MK et al (2014) Claudin-1 regulates intestinal epithelial homeostasis through the modulation of Notch-signalling. Gut 63:622–634CrossRefPubMedGoogle Scholar
  136. 136.
    Turgeon N, Blais M, Gagne JM, Tardif V, Boudreau F, Perreault N et al (2013) HDAC1 and HDAC2 restrain the intestinal inflammatory response by regulating intestinal epithelial cell differentiation. PLoS One 8:e73785CrossRefPubMedPubMedCentralGoogle Scholar
  137. 137.
    Garg P, Jeppsson S, Yang VW, Gewirtz AT, Merlin D, Sitaraman SV (2011) MMP-9 mediates colitis associated cancer in mice through Notch-1 via p53 activation O-21. Inflamm Bowel Dis 17:S9CrossRefGoogle Scholar
  138. 138.
    Da Costa LT, He T-C, Yu J, Sparks AB, Morin PJ, Polyak K et al (1999) CDX2 is mutated in a colorectal cancer with normal APC/β-catenin signaling. Oncogene 18:5010–5014CrossRefPubMedGoogle Scholar
  139. 139.
    Cosín-Roger J, Ortiz-Masiá D, Calatayud S, Hernández C, Álvarez A, Hinojosa J et al (2013) M2 macrophages activate WNT signaling pathway in epithelial cells: relevance in ulcerative colitis. PLoS One 8:e78128CrossRefPubMedPubMedCentralGoogle Scholar
  140. 140.
    Mikami T, Mitomi H, Hara A, Yanagisawa N, Yoshida T, Tsuruta O et al (2000) Decreased expression of CD44, alpha-catenin, and deleted colon carcinoma and altered expression of beta-catenin in ulcerative colitis-associated dysplasia and carcinoma, as compared with sporadic colon neoplasms. Cancer Interdiscip Int J Am Cancer Soc 89:733–740Google Scholar
  141. 141.
    Khare V, Dammann K, Asboth M, Krnjic A, Jambrich M, Gasche C (2015) Overexpression of PAK1 promotes cell survival in inflammatory bowel diseases and colitis-associated cancer. Inflamm Bowel Dis 21:287–296CrossRefPubMedPubMedCentralGoogle Scholar
  142. 142.
    Korinek V, Barker N, Moerer P, van Donselaar E, Huls G, Peters PJ et al (1998) Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nat Genet 19:379–383CrossRefPubMedGoogle Scholar
  143. 143.
    Mariadason JM, Bordonaro M, Aslam F, Shi L, Kuraguchi M, Velcich A et al (2001) Down-regulation of β-catenin TCF signaling is linked to colonic epithelial cell differentiation. Can Res 61:3465–3471Google Scholar
  144. 144.
    Phesse TJ, Buchert M, Stuart E, Flanagan DJ, Faux M, Afshar-Sterle S et al (2014) Partial inhibition of gp130-Jak-Stat3 signaling prevents Wnt–β-catenin–mediated intestinal tumor growth and regeneration. Sci Signal 7:ra92CrossRefPubMedGoogle Scholar
  145. 145.
    Xing Y, Chen X, Cao Y, Huang J, Xie X, Wei Y (2015) Expression of Wnt and Notch signaling pathways in inflammatory bowel disease treated with mesenchymal stem cell transplantation: evaluation in a rat model. Stem Cell Res Ther 6:101CrossRefPubMedPubMedCentralGoogle Scholar
  146. 146.
    Wee LH, Morad NA, Aan GJ, Makpol S, Ngah WZW, Yusof YAM (2015) Mechanism of chemoprevention against colon cancer cells using combined Gelam honey and Ginger extract via mTOR and Wnt/β-catenin pathways. Asian Pac J Cancer Prev 16:6549–6556CrossRefPubMedGoogle Scholar
  147. 147.
    Mashima T, Taneda Y, Jang M-K, Mizutani A, Muramatsu Y, Yoshida H et al (2017) mTOR signaling mediates resistance to tankyrase inhibitors in Wnt-driven colorectal cancer. Oncotarget 8:47902–47915CrossRefPubMedPubMedCentralGoogle Scholar
  148. 148.
    Inoki K, Ouyang H, Zhu T, Lindvall C, Wang Y, Zhang X et al (2006) TSC2 integrates wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell 126:955–968CrossRefPubMedGoogle Scholar
  149. 149.
    Wu D, Pan W (2010) GSK3: a multifaceted kinase in Wnt signaling. Trends Biochem Sci 35:161–168CrossRefPubMedGoogle Scholar
  150. 150.
    Valvezan AJ, Zhang F, Diehl JA, Klein PS (2012) Adenomatous polyposis coli (APC) regulates multiple signaling pathways by enhancing glycogen synthase kinase-3 (GSK-3) activity. J Biol Chem 287:3823–3832CrossRefPubMedGoogle Scholar
  151. 151.
    Dan HC, Cooper MJ, Cogswell PC, Duncan JA, Ting JP-Y, Baldwin AS (2008) Akt-dependent regulation of NF-κB is controlled by mTOR and Raptor in association with IKK. Genes Dev 22:1490–1500CrossRefPubMedPubMedCentralGoogle Scholar
  152. 152.
    Myant KB, Cammareri P, McGhee EJ, Ridgway RA, Huels DJ, Cordero JB et al (2013) ROS production and NF-κB activation triggered by RAC1 facilitate WNT-driven intestinal stem cell proliferation and colorectal cancer initiation. Cell Stem Cell 12:761–773CrossRefPubMedPubMedCentralGoogle Scholar
  153. 153.
    Ellenbroek SI, Collard JG (2007) Rho GTPases: functions and association with cancer. Clin Exp Metas 24:657–672CrossRefGoogle Scholar
  154. 154.
    Huang C-F, Chen L, Li Y-C, Wu L, Yu G-T, Zhang W-F et al (2017) NLRP3 inflammasome activation promotes inflammation-induced carcinogenesis in head and neck squamous cell carcinoma. J Exp Clin Cancer Res 36:116CrossRefPubMedPubMedCentralGoogle Scholar
  155. 155.
    Karki R, Malireddi RS, Zhu Q, Kanneganti T-D (2017) NLRC3 regulates cellular proliferation and apoptosis to attenuate the development of colorectal cancer. Cell Cycle 16:1243–1251CrossRefPubMedPubMedCentralGoogle Scholar
  156. 156.
    Zhang L, Mo J, Swanson KV, Wen H, Petrucelli A, Gregory SM et al (2014) NLRC3, a member of the NLR family of proteins, is a negative regulator of innate immune signaling induced by the DNA sensor STING. Immunity 40:329–341CrossRefPubMedPubMedCentralGoogle Scholar
  157. 157.
    Andresen L, Jørgensen V, Perner A, Hansen A, Eugen-Olsen J, Rask-Madsen J (2005) Activation of nuclear factor κB in colonic mucosa from patients with collagenous and ulcerative colitis. Gut 54:503–509CrossRefPubMedPubMedCentralGoogle Scholar
  158. 158.
    Kazi HA, Qian Z (2009) Crocetin reduces TNBS-induced experimental colitis in mice by downregulation of NFkB. Saudi J Gastroenterol 15:181–187CrossRefPubMedPubMedCentralGoogle Scholar
  159. 159.
    Sánchez-Fidalgo S, Villegas I, Rosillo MÁ, Aparicio-Soto M, de la Lastra CA (2015) Dietary squalene supplementation improves DSS-induced acute colitis by downregulating p38 MAPK and NFkB signaling pathways. Mol Nutr Food Res 59:284–292CrossRefPubMedGoogle Scholar
  160. 160.
    Lubbad A, Oriowo M, Khan I (2009) Curcumin attenuates inflammation through inhibition of TLR-4 receptor in experimental colitis. Mol Cell Biochem 322:127–135CrossRefPubMedGoogle Scholar
  161. 161.
    Zhu X, Liu Q, Wang M, Liang M, Yang X, Xu X et al (2011) Activation of Sirt1 by resveratrol inhibits TNF-α induced inflammation in fibroblasts. PLoS One 6:e27081CrossRefPubMedPubMedCentralGoogle Scholar
  162. 162.
    Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM, Donner DB (1999) NF-κB activation by tumour necrosis factor requires the Akt serine–threonine kinase. Nature 401:82–85CrossRefPubMedGoogle Scholar
  163. 163.
    Rozengurt E, Soares HP, Sinnet-Smith J (2014) Suppression of feedback loops mediated by PI3K/mTOR induces multiple overactivation of compensatory pathways: an unintended consequence leading to drug resistance. Mol Cancer Ther 13:2477–2488CrossRefPubMedPubMedCentralGoogle Scholar
  164. 164.
    Byles V, Covarrubias AJ, Ben-Sahra I, Lamming DW, Sabatini DM, Manning BD et al (2013) The TSC-mTOR pathway regulates macrophage polarization. Nat Commun 4:2834CrossRefPubMedPubMedCentralGoogle Scholar
  165. 165.
    Weichhart T, Costantino G, Poglitsch M, Rosner M, Zeyda M, Stuhlmeier KM et al (2008) The TSC-mTOR signaling pathway regulates the innate inflammatory response. Immunity 29:565–577CrossRefPubMedGoogle Scholar
  166. 166.
    Meng F, Liu L, Chin PC, D’Mello SR (2002) Akt is a downstream target of NF-κB. J Biol Chem 277:29674–29680CrossRefPubMedGoogle Scholar
  167. 167.
    Cao H, Xu E, Liu H, Wan L, Lai M (2015) Epithelial–mesenchymal transition in colorectal cancer metastasis: a system review. Pathol Res Pract 211:557–569CrossRefPubMedGoogle Scholar
  168. 168.
    Gulhati P, Bowen KA, Liu J, Stevens PD, Rychahou PG, Chen M et al (2011) mTORC1 and mTORC2 regulate EMT, motility and metastasis of colorectal cancer via RhoA and Rac1 signaling pathways. Cancer Res 71:3246–3256 (canres. 4058.2010) CrossRefPubMedPubMedCentralGoogle Scholar
  169. 169.
    Matos P, Jordan P (2006) Rac1, but not Rac1B, stimulates RelB-mediated gene transcription in colorectal cancer cells. J Biol Chem 281:13724–13732CrossRefPubMedGoogle Scholar
  170. 170.
    Han S-S, Yun H, Son D-J, Tompkins VS, Peng L, Chung S-T et al (2010) NF-κB/STAT3/PI3K signaling crosstalk in iMyc Eμ B lymphoma. Mol Cancer 9:97CrossRefPubMedPubMedCentralGoogle Scholar
  171. 171.
    Formentini L, Santacatterina F, de Arenas CN, Stamatakis K, López-Martínez D, Logan A et al (2017) Mitochondrial ROS production protects the intestine from inflammation through functional M2 macrophage polarization. Cell Rep 19:1202–1213CrossRefPubMedGoogle Scholar
  172. 172.
    Lu C-C, Huang W-S, Lee K-F, Lee K-C, Hsieh M-C, Huang C-Y et al (2016) Inhibitory effect of Erinacines A on the growth of DLD-1 colorectal cancer cells is induced by generation of reactive oxygen species and activation of p70S6K and p21. J Funct Foods 21:474–484CrossRefGoogle Scholar
  173. 173.
    Nenci A, Becker C, Wullaert A, Gareus R, van Loo G, Danese S et al (2007) Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature 446:557–561CrossRefPubMedGoogle Scholar
  174. 174.
    Nguyen PM, Putoczki TL, Ernst M (2015) STAT3-Activating Cytokines: a therapeutic opportunity for inflammatory bowel disease? J Interferon Cytokine Res 35:340–350CrossRefPubMedPubMedCentralGoogle Scholar
  175. 175.
    Nguyen AV, Wu YY, Liu Q, Wang D, Nguyen S, Loh R et al (2013) STAT3 in epithelial cells regulates inflammation and tumor progression to malignant state in Colon1. Neoplasia 15:998–1008CrossRefPubMedPubMedCentralGoogle Scholar
  176. 176.
    Laplante M, Sabatini DM (2013) Regulation of mTORC1 and its impact on gene expression at a glance. J Cell Sci 126:1713–1719CrossRefPubMedPubMedCentralGoogle Scholar
  177. 177.
    Lee SY, Lee SH, Yang EJ, Kim EK, Kim JK, Shin DY et al (2015) Metformin ameliorates inflammatory bowel disease by suppression of the STAT3 signaling pathway and regulation of the between Th17/Treg balance. PLoS One 10:e0135858CrossRefPubMedPubMedCentralGoogle Scholar
  178. 178.
    Croker BA, Krebs DL, Zhang J-G, Wormald S, Willson TA, Stanley EG et al (2003) SOCS3 negatively regulates IL-6 signaling in vivo. Nat Immunol 4:540–545CrossRefPubMedGoogle Scholar
  179. 179.
    Heinrich PC, Behrmann I, Serge H, Hermanns HM, Müller-Newen G, Schaper F (2003) Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J 374:1–20CrossRefPubMedPubMedCentralGoogle Scholar
  180. 180.
    Takahama M, Akira S, Saitoh T (2018) Autophagy limits activation of the inflammasomes. Immunol Rev 281:62–73CrossRefPubMedGoogle Scholar
  181. 181.
    Hosokawa N, Hara T, Kaizuka T, Kishi C, Takamura A, Miura Y et al (2009) Nutrient-dependent mTORC1 association with the ULK1–Atg13–FIP200 complex required for autophagy. Mol Biol Cell 20:1981–1991CrossRefPubMedPubMedCentralGoogle Scholar
  182. 182.
    Ganley IG, Lam DH, Wang J, Ding X, Chen S, Jiang X (2009) ULK1·ATG13·FIP200 complex mediates mTOR signaling and is essential for autophagy. J Biol Chem 284:12297–12305CrossRefPubMedPubMedCentralGoogle Scholar
  183. 183.
    Zaki MH, Vogel P, Body-Malapel M, Lamkanfi M, Kanneganti T-D (2010) IL-18 production downstream of the Nlrp3 inflammasome confers protection against colorectal tumor formation. J Immunol 185:4912–4920CrossRefPubMedPubMedCentralGoogle Scholar
  184. 184.
    Zaki MH, Boyd KL, Vogel P, Kastan MB, Lamkanfi M, Kanneganti T-D (2010) The NLRP3 inflammasome protects against loss of epithelial integrity and mortality during experimental colitis. Immunity 32:379–391CrossRefPubMedPubMedCentralGoogle Scholar
  185. 185.
    Schneider M, Zimmermann AG, Roberts RA, Zhang L, Swanson KV, Wen H et al (2012) The innate immune sensor NLRC3 attenuates Toll-like receptor signaling via modification of the signaling adaptor TRAF6 and transcription factor NF-κB. Nat Immunol 13:823–831CrossRefPubMedPubMedCentralGoogle Scholar
  186. 186.
    Linares JF, Duran A, Yajima T, Pasparakis M, Moscat J, Diaz-Meco MT (2013) K63 polyubiquitination and activation of mTOR by the p62-TRAF6 complex in nutrient-activated cells. Mol Cell 51:283–296CrossRefPubMedPubMedCentralGoogle Scholar
  187. 187.
    Park D, Jeong H, Lee MN, Koh A, Kwon O, Yang YR et al (2016) Resveratrol induces autophagy by directly inhibiting mTOR through ATP competition. Sci Rep 6:21772CrossRefPubMedPubMedCentralGoogle Scholar
  188. 188.
    Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB (2007) Bioavailability of curcumin: problems and promises. Mol Pharm 4:807–818CrossRefPubMedGoogle Scholar
  189. 189.
    Cottart CH, Nivet-Antoine V, Laguillier-Morizot C, Beaudeux JL (2010) Resveratrol bioavailability and toxicity in humans. Mol Nutr Food Res 54:7–16CrossRefPubMedGoogle Scholar

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Nutrition and Health SciencesUniversity of Nebraska-LincolnLincolnUSA

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