王照元高雄醫學大學附設醫院外科¤§腸癌症之...Jaw-Yuan Wang 大腸直腸癌分子致病機轉王照元高雄醫學大學附設醫院外科 Jaw-Yuan Wang Cancer

JawJaw--Yuan WangYuan Wang

大腸直腸癌分子致病機轉大腸直腸癌分子致病機轉

王照元高雄醫學大學附設醫院

外科


CancerCancer

A genetic disease, but in most cases, it is A genetic disease, but in most cases, it is not an inherited diseasenot an inherited disease

The genetic alterations that lead to most The genetic alterations that lead to most cancers arise in the DNA of a somatic cellcancers arise in the DNA of a somatic cell


Incidence and mortality of colorectal Incidence and mortality of colorectal carcinoma in the USA over the past 6carcinoma in the USA over the past 6 years years


Taiwan (2000): Male: 37.29; Female: 28.81


Gene Environment

GatekeeperGene

CaretakerGene

ExogenousAgents

EndogenousAgents and Mechanism

Causes of Genetic diseaseCauses of Genetic disease


大腸直腸癌腫瘤形成的模式，從正常黏膜經腺瘤階段進行至癌症，是由一連串基因的改變，積聚而成。研究顯示從正常大腸直腸黏膜變成大腸直腸腺性瘜肉平均所需時間約為十年，從腺性瘜肉成為大腸直腸癌則約需五年時間

大腸直腸癌的形成


Colorectal carcinoma develops along a ‘classical’ pathway outlined by Fearon and Vogelstein (1990)


Somatic mutations that cause Somatic mutations that cause sporadic colorectal sporadic colorectal neoplasianeoplasia

The 2 main types of genes The 2 main types of genes are playing a role in cancer are playing a role in cancer are are oncogenesoncogenes and and tumor tumor

suppressor genessuppressor genes


Functional Properties of Functional Properties of OncogenesOncogenes

Transformation events in cancer have Transformation events in cancer have been defined as initiation events or been defined as initiation events or progression eventsprogression events

OncogenesOncogenes encode proteins that control encode proteins that control cell proliferation, apoptosis, or bothcell proliferation, apoptosis, or both

Activated by structural alterations resulting Activated by structural alterations resulting from mutation or gene fusion or from mutation or gene fusion or amplification amplification


Products of Products of OncogenesOncogenes

Chromatin remodelersChromatin remodelers

Growth factorsGrowth factors

Growth factor receptorsGrowth factor receptors

Signal transducersSignal transducers

Transcription factorsTranscription factors

Apoptosis regulators Apoptosis regulators


OncogeneOncogene ActivationActivation

Chromosomal rearrangementsChromosomal rearrangements

chromosome inversions and translocations chromosome inversions and translocations

MutationsMutations

RASRAS oncogenesoncogenes ((KRAS, HRAS,KRAS, HRAS, and and NRASNRAS), ), which encode proteins with which encode proteins with guanosineguanosine-- nucleotidenucleotide––binding activity and intrinsic binding activity and intrinsic guanosineguanosine triphosphatasetriphosphatase activityactivity

Gene amplificationGene amplification

usually occurs during tumor progression usually occurs during tumor progression


30


Single nucleotide polymorphismsSingle nucleotide polymorphisms

55’’．．．．．．．．．．C C A T T G A CC C A T T G A C．．．．．．．．．．33’’55’’．．．．．．．．．．G G T A A C T GG G T A A C T G．．．．．．．．．．33’’

55’’．．．．．．．．．．C C G T T G A CC C G T T G A C．．．．．．．．．．33’’55’’．．．．．．．．．．G G C A A C T GG G C A A C T G．．．．．．．．．．33’’

Transition: Transition: pyridiminepyridimine pyridiminepyridimine (C,T)(C,T)purinepurine purinepurine (A, G)(A, G)

TransversionTransversion: : pyridiminepyridimine purinepurineTransition > Transition > transversiontransversion


FrequencyFrequency RareRare Common(>1% of a population)Common(>1% of a population)

Distribution in genomeDistribution in genome Primarily in genesPrimarily in genes Majority in interMajority in inter--genicgenic regionsregions

Density Density ~1,200 in OMIM*~1,200 in OMIM* ~15 million in genome(>5 million with ~15 million in genome(>5 million with frequency>10%)frequency>10%)

PenetrancePenetrance HighHigh Low (minority)Low (minority)

No effect (majority)No effect (majority)

Clinical utilityClinical utility Molecular Molecular diagnosisdiagnosis

Confers risk (still investigational)Confers risk (still investigational)

*Reported in On-line Mendelian Inheritance of Man(OMIM)data-base(http://www.ncbi.nlm.nib.gob/OMIM)

Critical Differences Between SNPs and Mutations

SNPMutation


EnvironmentEnvironment--Susceptibility Susceptibility InteractionInteraction

Carcinogens: chemicals or physicalCarcinogens: chemicals or physical

InitiationInitiation

Bind to DNA adduct, DNA changeBind to DNA adduct, DNA change

PromotionPromotion

Altered signal transduction, cell abnormal Altered signal transduction, cell abnormal proliferationproliferation


致癌物代謝酵素的致癌物代謝酵素的genetic genetic polymorphismpolymorphism

致癌物的代謝酵素致癌物的代謝酵素

PhasePhase--I enzyme: I enzyme: 將致癌化合物代謝成親電將致癌化合物代謝成親電子的代謝物子的代謝物, , 因而能活躍地與因而能活躍地與genomegenome的的 DNADNA

結合成結合成adduct, adduct, 以致造成基因的改變以致造成基因的改變, e.g. , e.g. cytochromecytochrome pp--450450--dependent dependent monooxygenasemonooxygenase: CYP1A1: CYP1A1

PhasePhase--II enzyme:II enzyme:將致癌化合物轉變成親水將致癌化合物轉變成親水性的代謝物性的代謝物, e.g. Glutathione, e.g. Glutathione--SS--transferasetransferase

能將能將polycyclic aromatic polycyclic aromatic hydrogenasehydrogenase解毒解毒


致癌物代謝酵素的致癌物代謝酵素的genetic genetic polymorphismpolymorphism

只有暴露於低劑量致癌物的情況下只有暴露於低劑量致癌物的情況下,,基因多型性基因多型性與致癌關係才會明顯有意義與致癌關係才會明顯有意義

調控致癌物代謝之某種特殊基因型態調控致癌物代謝之某種特殊基因型態,,由於表現由於表現率相當低率相當低,,因此病例數要相當大才能看出關聯性因此病例數要相當大才能看出關聯性

致癌物與致癌物代謝酵素常是多種混在一起相致癌物與致癌物代謝酵素常是多種混在一起相互作用互作用

致癌物的解毒與活化在不同個體間的差異並不致癌物的解毒與活化在不同個體間的差異並不是完全由基因所決定的是完全由基因所決定的


Genetic Polymorphism and Genetic Polymorphism and Colorectal CancersColorectal Cancers

活躍的活躍的CYP1A1CYP1A1酵素的基因型確實與大腸直腸癌的致癌酵素的基因型確實與大腸直腸癌的致癌過程有關過程有關

具快速具快速NN--acetyltransferaseacetyltransferase (NAT) (NAT) 酵素的基因型會更有酵素的基因型會更有效地將肉類的效地將肉類的heterocyclic aromatic aminesheterocyclic aromatic amines活化活化,,這些人這些人較易得到大腸直腸癌較易得到大腸直腸癌

十字花科蔬菜之所以能預防大腸直腸癌乃是透過十字花科蔬菜之所以能預防大腸直腸癌乃是透過 GlutathioneGlutathione--SS--transferasetransferase (GST)(GST)活性增加所致活性增加所致

MethylenetetrahydrofolateMethylenetetrahydrofolate reductasereductase (NTHFR) (NTHFR) 的遺傳的遺傳多型性與大腸直腸癌有相關多型性與大腸直腸癌有相關: variant homozygous (TT): : variant homozygous (TT):

發生率最低發生率最低, variant heterozygous (CT), wild type , variant heterozygous (CT), wild type homozygous (CC)homozygous (CC)


飲食因素(高脂肪, 低纖維; 抽煙)

a) 食物纖維: 第一個主要理論快速通過時間會降低致癌物質與大腸黏膜接觸的時間

b) 食物脂肪: 第二個主要理論但大腸癌與fat-protein consumption無法平行

c) 食物糖分 d) 腸道菌叢的改變(Alternation in bowel microflora)

e) DeVita 認為目前低脂高纖的飲食是明智的f)卡路里或酒精攝取過量; 肥胖g)膽酸分泌


Bile acids and colon cancer (Reddy et al.,1977; Kulkarni et al.,1982; Ksndell et al.,1991; Carol et al.,1999;Glinghammar et al., 2002; Lechner et al., 2002; Wachs et al., 2005):

Oxidative stress

DNA damage

Mitochondrial membrane instabilityBile acid possibly play an important intermediate role in the cell proliferation, but the mechanism is not well understood (European Journal of Cancer, 1956).

Synthesis0.4-1.2 mmol/Day

Small Bowel

Colon


肥胖、體能活動、以及能量攝取肥胖、體能活動、以及能量攝取

肥胖對大腸直腸癌的影響在男性比女性明肥胖對大腸直腸癌的影響在男性比女性明顯顯

體能活動較旺盛者罹患大腸直腸癌的機會體能活動較旺盛者罹患大腸直腸癌的機會較低：大腸直腸黏膜的較低：大腸直腸黏膜的PGE2 PGE2 濃度較低濃度較低

個人的總能量攝取與大腸直腸癌有正相關個人的總能量攝取與大腸直腸癌有正相關


Gene name APC K-ras p53Adenomatous polyposis coliDiscovery

20-30% humancancers

50% human Solid tumors

Gatekeeper gene, tumor suppressor gene

Proto- Oncogene, GTP binding protein

Tumor suppressor gene, transcription factor

Function

Mutational

Hot spots

Codons 1286~1513

Codons 12,13& 61

Exons 5 ~ 8


APC K-ras p53MutationsIncidence

52 /118 (44.1%) 54 /118 (45.8%) 43 /118 (36.4%)

MutationsType

29/118 missense10/118 frameshift6/118 nonsense 6/118 silent 1/118 deletion

44/118 missense3/118 frameshift3/118 silent 2/118 nonsense

30/118 missense6/118 frameshift6/118 silent 3/118 nonsense

Hot spots(cases)

1259 (3), 1263 (2), 1285 (2), 1288 (2), 1296 (2), 1326 (2),1331 (2), 1404 (2), 1560 (2), 1565 (2), 1581 (2), 1582 (2), 1605 (2)

12 (14), 13 (10), 15 (8), 18 (3), 20 (3), 21 (2), 27 (2), 30 (2)

175 (3), 194 (2), 207 (2), 209 (5), 245 (2), 248 (2), 267 (2), 273 (2), 282 (2)

New Finding

1259，1263，1285， 1560，1565，1581， 1582，1605並不在

mutation cluster region

突變熱點中30% （14/47）是在codon 15，另外codons 18，

20，21，27，30是未曾在CRC報告過

codons 194，207， 267，282是文獻未曾在

大腸直腸癌上發現的

Results of KMUH


12.2%

17.1%

9.8%26.8%

17.1%

12.2% 4.9%APC

K-ras

p53

APC + K-ras

APC + p53

K-ras + p53 APC + K-ras + p53

Mutation Frequency of APC, K-ras, p53 in Taiwanese CRC


Our data Smith et al.APC 44.1% 60%K-ras 45.8% 30%P53

Only one gene mutation

36.4%

41.3%

61.3%

38.7%

Three gene mutations 5% 6%≧1 gene mutations 77.1% 88.7%

本研究 Smith et al.APC missense 突變 nonsense 突變、frameshift

K-ras

Combine

codon 15

most APC+K-ras

codon 12、codon 13

most APC+p53


0

10

20

30

40

50

60

A B C D

Dukes' stage

Tum

ors

anal

yze

d (

%)

APC

K-ras

p53


Microarray Ratio Northern blotting ratio GenBank Identity/Symbol CRC-related GenBank

(carcinoma/adenoma/normal) (carcinoma/adenoma/normal) Accession number

(41.35/26.12/1) (43.86/21.12/1) Capping protein (actin filament) muscle Z-line, alpha 1/(-) NM_006135 CAPZ1

(18.26/4.87/1) (24.65/4.02/1) Ecotropic viral integration site 2B/EVI2B Unknown NM_006495(16.88/4.78/1) (11.24/3.27/1) ATPase, Ca++ transporting, cardiac muscle, (-) NM_001681

slow twitch 2/ATP2A2(11.29/4.95/1) (13.76/4.36/1) KIAA0176 protein/ KIAA0176 (-) D79998(10.35/6.05/1) (10.97/4.80/1) S100 calcium binding protein, beta (neural)/S100B (-) NM_006272(7.58/3.73/1) (8.88/3.38/1) Kallikrein 7 (chymotryptic, stratum corneum)/KLK7 (-) NM_005046(6.54/4.05/1) (7.25/3.71/1) Decay accelerating factor for complement (+) NM_000574

(CD55, Cromer blood group system)/DAF(5.75/3.90/1) (6.08/3.26/1) Guanine nucleotide binding protein (G protein), (+) NM_006098

beta polypeptide 2-like 1/G protein(5.36/2.54/1) (20.75/3.75/1) ELAV (embryonic lethal, abnormal vision, Drosophila)-(-) NM_021952

like 4 (Hu antigen D)/EVLAVL4 (5.09/2.48/1) (32.67/4.33/1) Transmembrane 4 superfamily member 3/TM4SF3 (+) NM_004616 (4.85/3.01/1) (5.98/3.23/1) Kallikrein 1, renal/pancreas/salivary/KLK1 (+) NM_002257 (4.23/2.05/1) (8.08/2.56/1) Keratin 4/KRT4 (-) NM_002272 (3.96/3.03/1) (19.46/2.75/1) Formin binding protein 3/FNBP3 (-) BC027178 (3.59/2.12/1) (3.29/2.05/1) Haptoglobin/HP (+) NM_005143(3.56/2.28/1) (6.81/3.04/1) Homo sapiens chromosome 21q22.1 anonymous Unknown AF003738

mRNA sequence/chromosome 21q22.1(3.48/3.01/1) (5.51/3.20/1) Solute carrier family 25 (mitochondrial carrier; (-) NM_001151

adenine nucleotide translocator), member 4/SLC25A4(3.44/2.43/1) (20.67/4.59/1) Peptidylprolyl isomerase B (cyclophilin B)/PPIB (-) NM_000942(3.39/2.17/1) (4.34/2.32/1) H2A histone family, member Y/H2AFY (-) NM_004893(3.28/2.29/1) (3.06/2.13/1) Homo sapiens DMR protein mRNA/DMR Unknown AF327354(3.18/2.10/1) (4.21/2.29/1) Nerve growth factor receptor (-) NM_00250

(TNFR superfamily, member 16)/NGFR(3.17/2.31/1) (3.28/2.45/1) Laminin receptor 1 (67kD, ribosomal protein SA) (+) NM_002295

/LAMR1(3.09/2.52/1) (3.17/2.30/1) Small inducible cytokine subfamily A (Cys-Cys), (-) NM_004591

member 20/SCYB11(3.02/2.18/1) (3.82/2.38/1) Eukaryotic translation elongation factor 1 alpha 1 (+) NM_001402

/EEF1A1


Gene OntologyGene Ontology


Possible invasion and metastasis-associated genes

Possible invasion and Possible invasion and metastasismetastasis--associated genesassociated genes

Capping protein muscle ZCapping protein muscle Z--line, alpha 1line, alpha 1 is involved in cell is involved in cell motilitymotility

ATPaseATPase, Ca, Ca++++ transporting, slow twitch 2 transporting, slow twitch 2 andand lamininlaminin receptor 1 are involved cell adhesionreceptor 1 are involved cell adhesion

ChemokineChemokine ligandligand 2020 is involved in is involved in chemokinechemokine activityactivity

Guanine nucleotide binding protein Guanine nucleotide binding protein ββ--subunitsubunit and and nerve nerve growth factor receptorgrowth factor receptor are involved in signal transductionare involved in signal transduction

Keratin 4Keratin 4 is involved in cytoskeleton organization is involved in cytoskeleton organization

KallikreinKallikrein 11, , kallikreinkallikrein 77, , haptoglobinhaptoglobin and and H2A H2A histonehistone family, member Yfamily, member Y are involved in proteolysis are involved in proteolysis

S100 calcium binding protein, betaS100 calcium binding protein, beta is involved in cell is involved in cell proliferationsproliferations


Genes are demonstrated to be considerably correlated to tumor

invasion and metastasis

Genes are demonstrated to be Genes are demonstrated to be considerably correlated to tumor considerably correlated to tumor

invasion and metastasis invasion and metastasis

Laminin receptor 1 that is overexpressed on the tumor cell surface in a variety of cancers plays a major role in tumor aggressiveness and metastasis

Kallikrein 7 may play an important role in invasion and metastasis of ovarian and cervical cancers

A haptoglobin-related glycoprotein is implicated in tumor progression and metastasis of colorectal cancers

S100 calcium binding protein, beta appears to be the most appropriate tumor marker for newly occurred melanoma metastases


Functional categories of upFunctional categories of up--regulated or downregulated or down-- regulated genes in Colorectal Cancerregulated genes in Colorectal Cancer

15 14

62

2 3

107

4 4

29

1 1

74

transcription transcription,DNA-dependent

metabolism nucleosome myosin receptor bindingactivity

cytokine activity

Functional (Term)

Gen

e Ex

pres

sed

(N)

-

down-regulated up-regulated


Gene Expression

Pathwayanalysis

Gene Ontology(GO)

MAPPFinder/GoMiner

Spotfire &&GenMAPPand DAVID

大腸直腸癌癌化之分子

模式假說

代謝途徑的分析

脂肪酸代謝膽酸代謝醣類水解缺氧機轉


Gene Description Function

EHHADH enoyl-Coenzyme A, hydratase/3- hydroxyacyl Coenzyme A dehydrogenase

catalyzing the second and third step of peroxisomal fatty acid beta-oxidation of very long chain fatty acids, but not bile intermediates

ECHS1 enoyl Coenzyme A hydratase, short chain, 1, mitochondrial

The second step in mitochondrial fatty acid beta- oxidation

GCDH glutaryl-Coenzyme A dehydrogenase glutaryl-CoA dehydrogenase, flavoprotein dependent, lysine oxidation

COX2 acyl-Coenzyme A oxidase 2, branched chain

peroxisomal branched chain trihydroxypristanoyl-CoA oxidase

ACADS acyl-Coenzyme A dehydrogenase, C-2 to C-3 short chain precursor

catalyzing the initial step of the mitochondrial fatty acid beta-oxidation pathway

CPT1B carnitine palmitoyltransferase 1B trans-esterification of medium and long chain fatty acyl,chains converting palmitoyl carnitine into palmitoyl-CoA (palmitoyl-CoA shuttle)

ACSL5 acyl-CoA synthetase long-chain family member 5

converting free long-chain fatty acids into fatty acyl CoA esters

CYP4A11 cytochrome P450, family 4, subfamily A, polypeptide 11

hydroxylation of medium chain fatty acid such as laurate and myristate

Normal subjectNormal subject CColon cancer patientolon cancer patient

EHHADH ECHS1 GCDH

COX2 ACADS CPT1B

ACSL5 CYP4A11 β-actin

EHHADH ECHS1 GCDH

COX2 ACADS CPT1B

ACSL5 CYP4A11 β-actin

Fatty acid metabolism relevant gene


Linoleic acid (n-6 PUFAs)


α-D-Glucose

β-D-Glucose

GLAM

HK1, GCK

HK1, GCKβ-D-Glucose-6P

α-D-Glucose-6P(aerobic decarboxylation)

β-D-Glucose-6PGPI

GPIGPI

β-D-Fructose-1,6P2

PFKLPFKMPFKP

FBP1FBP2

Glyceraldehyde-3P

Glycerate-1,3P2

Glycerate-3P

Glycerate-2P

Phosphoenol-Pyruvate

Pyruvate

α-D-Glucose-1P

ALDOA, ALDOB ,ALDOC

GAPD

ACYP1ACYP2

PGK1PGK2

Glycerate-2,3P2

PGM1, PGM3

PGAM1, PGAM2, BPGM

ENO1, ENO2, ENO3

PKLR, PKM2

L-LactateLDHA, LDHB, LDHC

G6PC

TPI1Glycerone-P

PGAM1, PGAM2, BPGM

PGAM1, PGAM2, BPGM

Glucose

GLUT1GLUT3

Cell Membrane

1. HK 1: Hexokinase2. GPI: Phosphoglucose isomerase3. PFKL: Phosphofructokinase4. ALDOB: Aldoase5. TPI 1: Triose phosphate isomerase6. GAPD: Glyceraldehyde 3-phosphate

dehydrogenase7. PGK 1: Phosphoglycerate kinase8. PGAM 1: Phosphoglycerate mutase9. ENO 1: Enolase10. PKLR: Pyruvate kinase

Glycolytic pathway


020406080

100120140160180200

6 h 12 h 16 h 20 h

Treatment Time

Cel

l pro

lifer

atio

n (%

of c

ontro

l)Untreated-Control SW-480 cell line treated with 15 mM D-(+)-Glucose SW-620 cell line treated with 15 mM D-(+)-Glucose

Cell proliferation by D-(+)-glucose

SW480 cell: the viability values were 25, 49, 56, and 68%SW620 cell: the viability values were 32, 52, 67, and 78%


Activation of Activation of glycolysisglycolysis by by DD--(+)(+)--glucoseglucose

SW480 cell line SW480 cell line SW620 cell line SW620 cell line

TimesTimesConcentration (mg/dl) Concentration (mg/dl) Increase (%) Increase (%) p*p* Concentration Concentration

(mg/dl) (mg/dl)

Increase (%) Increase (%) p* p*

6 h 6 h 20.39 20.39 ±±

0.06 0.06 3.25 3.25


KEGG Pathway


Hypoxia Chamber

Normoxia( 5% CO2 and

21% O2)

Hypoxia (1% O2，5% CO2

and 94% N2)

Hypoxicrelated-genes

Glycolyticrelated-genes

Molecular Mechanism in Colorectal Cancer

SW480 cell&

SW620 cell

24 hrs & 48 hrs

Tumor tissue


Hypoxia(Hypoxia(缺氧缺氧))與乳酸與乳酸(lactate)(lactate)關聯性的分析結果關聯性的分析結果

SW480 cell lineSW480 cell line24 hrs24 hrs: : 2.242.24倍倍48 hrs: 3.3648 hrs: 3.36倍倍

SW620 cell lineSW620 cell line24hrs: 3.0624hrs: 3.06倍倍48 hrs: 3.1748 hrs: 3.17倍倍


HIFHIF--11αα和和GLUT1GLUT1基因一致性基因一致性表現的分析結果表現的分析結果

HIFHIF--11αα

Gene expression Gene expression ratioratio 1.02 1.36 1.08 1.26 1.76 1.23 1.871.02 1.36 1.08 1.26 1.76 1.23 1.87 6.37 2.42 2.25 7.63 2.306.37 2.42 2.25 7.63 2.30

GLUT1GLUT1

Gene expression Gene expression ratioratio 1.89 2.37 1.91 1.86 2.48 1.79 1.1.89 2.37 1.91 1.86 2.48 1.79 1.98 3.89 2.34 2.32 4.43 2.5898 3.89 2.34 2.32 4.43 2.58

ββ--actinactin

SW480 cell24 hrs

SW620 cell24 hrs

SW480 cell48 hrs

SW620 cell48 hrs

120 bp

168 bp

245 bp

Contr

ol

Hypo

xia

Norm

oxia

Contr

ol

Hypo

xia

Norm

oxia

Contr

ol

Hypo

xia

Norm

oxia

Contr

ol

Hypo

xia

Norm

oxia

HIF-1α和GLUT1基因呈現一致性的上升表現

Results: (2)


比較比較SW480SW480和和SW620SW620細胞株其細胞株其HIFHIF--11αα基基因表現情形因表現情形

SW480 cell lineSW480 cell line24 hrs: 24 hrs: 1.261.26倍倍48 hrs: 48 hrs: 2.632.63倍倍

SW620 cell lineSW620 cell line24hrs: 24hrs: 1.431.43倍倍48 hrs: 48 hrs: 3.323.32倍倍


比較比較SW480SW480和和SW620SW620細胞株其細胞株其GLUT1GLUT1基基因表現情形因表現情形

SW480 cell lineSW480 cell line24 hrs: 24 hrs: 1.241.24倍倍48 hrs: 48 hrs: 1.661.66倍倍

SW620 cell lineSW620 cell line24hrs: 24hrs: 1.391.39倍倍48 hrs: 48 hrs: 1.721.72倍倍

Genes with altered expression Genes with altered expression levels in CRC were mainly levels in CRC were mainly

associated with fatty acid and associated with fatty acid and glucose metabolic pathways, in glucose metabolic pathways, in

addition to hypoxic pathway addition to hypoxic pathway speculated to have an important speculated to have an important

role linked to carcinogenesis role linked to carcinogenesis


Thank You For Your AttentionThank You For Your Attention

投影片編號 1Cancer投影片編號 3投影片編號 4投影片編號 5投影片編號 6投影片編號 7投影片編號 8投影片編號 9The 2 main types of genes are playing a role in cancer are oncogenes and tumor suppressor genes 投影片編號 11Functional Properties of Oncogenes Products of Oncogenes Oncogene Activation 投影片編號 15投影片編號 16投影片編號 17投影片編號 18投影片編號 19投影片編號 20投影片編號 21投影片編號 22投影片編號 23投影片編號 24投影片編號 25投影片編號 26投影片編號 27投影片編號 28投影片編號 29投影片編號 30投影片編號 31投影片編號 32投影片編號 33投影片編號 34投影片編號 35投影片編號 36投影片編號 37投影片編號 38投影片編號 39投影片編號 40投影片編號 41投影片編號 42投影片編號 43投影片編號 44投影片編號 45投影片編號 46投影片編號 47投影片編號 48投影片編號 49投影片編號 50投影片編號 51投影片編號 52投影片編號 53投影片編號 54Possible invasion and metastasis-associated genesGenes are demonstrated to be considerably correlated to tumor invasion and metastasis 投影片編號 57投影片編號 58投影片編號 59Functional categories of up-regulated or down-regulated genes in Colorectal Cancer投影片編號 61投影片編號 62投影片編號 63投影片編號 64投影片編號 65投影片編號 66投影片編號 67投影片編號 68投影片編號 69投影片編號 70投影片編號 71投影片編號 72投影片編號 73Activation of glycolysis by D-(+)-glucose投影片編號 75投影片編號 76投影片編號 77投影片編號 78Hypoxia(缺氧)與乳酸(lactate)關聯性的分析結果 HIF-1α和GLUT1基因一致性表現的分析結果比較SW480和SW620細胞株其HIF-1α基因表現情形比較SW480和SW620細胞株其GLUT1基因表現情形 Genes with altered expression levels in CRC were mainly associated with fatty acid and glucose metabolic pathways, in addition to hypoxic pathway speculated to have an important role linked to carcinogenesis Thank You For Your Attention�

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