ActinEpub

Invited critical review

ACTB in cancer

Chunmei Guo a ,Shuqing Liu b ,Jiasheng Wang a ,Ming-Zhong Sun a ,?,Frederick T.Greenaway c

a Department of Biotechnology,Dalian Medical University,Dalian 116044,China

b Department of Biochemistry,Dalian Medical University,Dalian 116044,China

c

Carlson School of Chemistry and Biochemistry,Clark University,Worcester,MA 01610,USA

a b s t r a c t

a r t i c l e i n f o Article history:

Received 25September 2012

Received in revised form 27November 2012Accepted 1December 2012

Available online 22December 2012Keywords:ACTB Function Tumor Cancer

Beta-actin (ACTB)has traditionally been regarded as an endogenous housekeeping gene and has been widely used as a reference gene/protein in quantifying expression levels in tumors.However,ACTB is closely associ-ated with a variety of cancers and accumulating evidence indicates that ACTB is de-regulated in liver,mela-noma,renal,colorectal,gastric,pancreatic,esophageal,lung,breast,prostate,ovarian cancers,leukemia and lymphoma.ACTB is generally found to be up-regulated in the majority of tumor cells and tissues.The abnor-mal expression and polymerization of ACTB and the resulting changes to the cytoskeleton are revealed to be associated with the invasiveness and metastasis of cancers.The current review explores relevant mecha-nisms,integrates current understandings,and provides suggestions for future studies of the roles of ACTB in tumors.

?2012Published by Elsevier B.V.

Contents 1.Introduction ...............................................................392.

The association of ACTB with tumors ...................................................402.1.ACTB is potentially involved in liver cancer development and metastasis ..................................402.2.ACTB is potentially correlated with melanoma ...........................................402.3.ACTB is potentially involved in renal cancer development ......................................402.4.ACTB is de-regulated in tissues from colorectal cancer ........................................402.5.ACTB mRNA over-expression is associated with gastric cancer ....................................412.6.ACTB is not suitable as a reference gene for pancreatic cancer and esophageal cancer .........................412.7.ACTB is closely associated with lung cancer .............................................412.8.ACTB might promote breast cancer cell proliferation and tumor aggressiveness ............................412.9.ACTB is associated with prostate cancer and ovarian cancer .....................................412.10.ACTB is a potential indictor and therapeutic target for leukemia ...................................412.11.ACTB is associated with drug-resistance of lymphoma ........................................423.Potential mechanisms of action of ACTB in cancer .............................................424.Conclusions ...............................................................43Acknowledgements ..............................................................43References .........................................

(43)

1.Introduction

Beta-actin (ACTB)is an abundant and highly conserved cytoskeleton structural protein that is widely distributed in all eukaryotic cells and plays critical roles in cell migration,cell division,embryonic development,wound healing,immune response and gene expression [1–4].These

functions are attributed to the ability of ACTB to form ?laments that can be rapidly assembled and disassembled in response to the needs of cells [2,3,5].Cell migration is commonly driven by ACTB polymerization at the leading edge,which provides the protrusive forces that push the membrane forward [6–8].ACTB is generally regarded as a constitutive housekeeping gene with the assumption that ACTB expression is usually unaffected by most experimental or physiological conditions and it has therefore been widely used as a reference for quanti ?cation of changes of genes/proteins in cells and tissues [6–8].However,since it is a multifunctional gene/protein,the utilization of ACTB as a reference

Clinica Chimica Acta 417(2013)39–44

?Corresponding author at:Department of Biotechnology,Dalian Medical University,Dalian 116044,China.Tel.:+8641186110445.

E-mail address:mxs288@https://www.wendangku.net/doc/ef4429617.html, (M.-Z.

Sun).0009-8981/$–see front matter ?2012Published by Elsevier B.V.

https://www.wendangku.net/doc/ef4429617.html,/10.1016/https://www.wendangku.net/doc/ef4429617.html,a.2012.12.012

Contents lists available at SciVerse ScienceDirect

Clinica Chimica Acta

j ou r n a l h o m e p a g e :w w w.e l s e v i e r.c o m /l o c a t e /c l i n c h i m

gene/protein has been challenged[9,10].ACTB levels are highly differ-entially regulated in a variety of types of cells/tissues under certain met-abolic conditions.Distinct correlations between ACTB levels,ACTB polymerization,ACTB cytoskeleton organization and invasiveness and metastatic capacity of tumor cells[2–4,8,11],suggest that ACTB plays roles in cancer pathogenesis that are not yet understood.ACTB was found to be differentially expressed in liver,melanoma,renal,colorec-tal,gastric,pancreatic,esophageal,lung,breast,prostate,ovarian can-cers,leukemia and lymphoma under certain conditions[12–15], which suggests that1)ACTB might be unsuitable for gene/protein level normalization in certain types of tumor cells and clinical samples;

2)the utilization of ACTB mRNA as a control RNA should be chosen cau-tiously;and3)ACTB may play a role in cancer pathogenesis.

The current paper summarizes recent research progress in under-standing the roles of ACTB in tumors and discusses relevant mecha-nisms.ACTB de-regulation is usually detected in tumors and affects the polymerization of ACTB at the leading edge in tumor cells,accel-erating tumor formation,invasion and metastasis.However,the de-tailed mechanisms of action of ACTB in tumor progression are still unclear and worthy of study.ACTB de-regulation in certain tumors highlights the signi?cant role of this housekeeping gene in cell func-tion and provides useful insights for future study of it.

2.The association of ACTB with tumors

2.1.ACTB is potentially involved in liver cancer development and metastasis

Hepatocellular carcinoma(HCC)ranks third amongst all deaths from cancers,killing~650,000people annually[16,17].The major risk factor for HCC development is liver cirrhosis following chronic hepatitis viral infections from hepatitis B virus(HBV)and hepatitis C virus(HCV)[1,18].

ACTB is up-regulated in liver cancer tissues.Gene microarray and quantitative real-time RT-PCR(qRT-PCR)analyses showed that ACTB is up-regulated two-to three-fold in highly advanced stages of HCV-induced HCC[1].Comparison of ACTB gene levels in normal liver tissues,and in paired tumor and non-tumor tissues of patients with HBV-related HCC indicted that ACTB is differentially expressed in these tissues,which can lead to misinterpretation of gene expres-sion results[18].ACTB is thus unsuitable for qRT-PCR normalization in such tissues.

The genes favoring progression of metastasis most probably originate in primary tumors.It is becoming a routine strategy to search for bio-markers that can be used for clinical prognosis by comparing gene ex-pression levels in tumor samples or in cells with and without invasion/ metastasis.Several studies have shown a correlation of ACTB with cancer cell motility and metastasis potential.ACTB was de-regulated in different TNM stages and degrees of tumor invasiveness of HCC[18,19]and was differentially expressed in paired malignant and non-malignant tissues from untreated patients with HCC.ACTB levels did not correlate with pa-tient age or gender,or with tumor size,number,or stage,or with cirrhotic status,but did signi?cantly correlate with venous invasion,which is a histopathological feature of HCC invasiveness.ACTB was signi?cantly up-regulated in HCC with more highly invasive tumors,consistent with ACTB de-regulation in HCC carcinogenesis and progression[19].Re-sults from separate groups indicated that ACTB mRNA levels were up-regulated2.8-fold and4.8-fold in liver carcinoma metastatic tissues compared with normal liver tissues[20,21].ACTB up-regulation was also found in N1S1rat hepatoma samples[22].These results suggest that ACTB is not a suitable internal control for comparative gene expres-sion studies in HCC,cirrhosis and normal tissues.In hepatoma Morris 5123cells,which have increased cell locomotion and higher invasiveness compared to parental cells,ACTB was remarkably increased and there was an increased level of ACTB polymerization[4,8].

These results suggest that ACTB might be essential for hepatoma oncogenesis.ACTB gene levels might serve as a diagnostic indicator for HCC as ACTB up-regulation is closely associated with liver cancer growth and metastasis although the exact relationship between this novel activity of ACTB and tumor metastasis remains to be elucidated. It is also possible that changes in ACTB expression and cytoskeleton reorganization might be involved in tumor malignancy,in which case it could be possible to?nd anti-tumor drugs affecting cell motility.

2.2.ACTB is potentially correlated with melanoma

One of the most malignant tumors,melanoma,is steadily increas-ing and has a high mortality rate.Once it metastasizes,the5-year sur-vival rate of melanoma is below10%[12].

ACTB has been associated with the invasiveness of melanoma cells. cDNA array analyses of different genes expressed in two melanoma cells,1C8(a non-invasive melanoma cell)and T1C3(an invasive mela-noma cell),derived from the same melanoma patient indicated that the mRNA level of ACTB in T1C3was twofold higher than in1C8melanoma cells[13].ACTB is not appropriately utilized as a reference gene/protein for melanoma as it was signi?cantly de-regulated in tumor cells obtained from the same patient or in highly heterogeneous cellular sub-populations of same pathological origin.This points out that the selec-tion of an appropriate internal control for gene or protein expression analyses must take into account the type of human cancer being studied.

2.3.ACTB is potentially involved in renal cancer development

Renal cell carcinoma(RCC)is a highly metastatic urological tumor accounting for~3%of adult cancers.RCC is clinically asymptomatic and usually detected in the course of routine ultrasonic scans[14,15]. The lack of diagnostic and prognostic markers complicates its early de-tection,so that most cancers have metastasized at the time of diagnosis.

The clear cell subtype of RCC(ccRCC)has~75%incidence of malig-nant RCC with poor prognosis[15].RT-PCR results indicate that ACTB was signi?cantly increased in tissues from25ccRCC patients compared to matched non-malignant tissues,but that the ACTB level did not de-pend on patients'age or gender,or the tumor stage[23].ACTB protein was also de-regulated in RCC cell lines and tumor tissues,and ACTB pro-tein levels varied among established RCC lines,with higher levels being seen in malignant renal tissues in comparison with normal tissues[24]. Thus ACTB might be involved in RCC and the corresponding regulation mechanisms need to be clari?ed.

2.4.ACTB is de-regulated in tissues from colorectal cancer

Colorectal cancer(CRC)is the third most common cancer.It affects almost a million people annually,and causes approximately500,000 deaths.Despite its high incidence,CRC has a better prognosis with a 50%mortality rate[16,25,26].

Utilizing a model-based variance estimation strategy to select ref-erence genes for qRT-PCR data,Andersen et al.found that ACTB was unsuitable for normalization of colon and bladder cancers[27].A sim-ilar conclusion was reached for ACTB expression in colorectal tumors matched against normal specimens[28,29],and ACTB was also found to be signi?cantly de-regulated in CRC tissues[9,29].Microarray data and Western blot analysis revealed that ACTB protein levels de-creased four-fold in MDA7-transduced CRC DLD-1cells compared with untransduced DLD-1cells[20].MDA7is a tumor suppressor that can induce apoptosis and dismantle the cytoskeletal make-up of cancer cells.This?nding indicates that ACTB may be involved in CRC carcinogenesis[30].The general conclusion of such?ndings is that one should be cautious in using ACTB as an internal reference gene/protein for CRC studies.

40 C.Guo et al./Clinica Chimica Acta417(2013)39–44

2.5.ACTB mRNA over-expression is associated with gastric cancer

Gastric cancer is the fourth most common cancer.Survival from gastric cancer is poor as patients are often diagnosed at highly advanced stages [31].ACTB was proved to be involved in the malignancy of gastric cancer.

ACTB was proved to be an unsuitable endogenous reference gene for gene expression studies of gastric cancer based on the fact that ACTB mRNA levels showed a1.4-fold expression increase in gastric carcinoma tissues compared to matched paracancerous normal tissues[21]. Assessing the suitability of six possible reference genes by qRT-PCR in 20paired gastric cancer tissues and matched paracancerous tissues and six gastric cancer cell lines,Rho et al.revealed that ACTB had a rel-atively lower stability unsuitably used as single reference gene.ACTB was more highly expressed in gastric tissues than in cancer cell lines (SNU-216,SNU-638,SNU-719,AGS,MKN-28and KATOIII)[31].Higher ACTB levels were also found in gastric cancer tissues than in AGS/ SNU-638gastric cancer cells[9],opposite to the expectation that cancer cells are usually more activated in metabolism and eventually display higher transcription activities[31].

2.6.ACTB is not suitable as a reference gene for pancreatic cancer and esophageal cancer

The use of ACTB as an endogenous reference for gene expression studies of pancreatic cancer and esophageal cancer has also been questioned[21].ACTB is up-regulated in pancreatic carcinomas at both RNA and protein levels.mRNA levels of ACTB exhibited a 1.7-fold increase in pancreatic carcinoma tissues over normal pancre-atic tissues[21],which indicates a role for ACTB in pancreatic cancer.

Esophageal squamous cell carcinoma(ESCC)and esophageal ade-nocarcinoma are the major histological types of esophageal cancers found in China and in Western countries[32].Two-dimensional electrophoresis-MALDI-TOF-MS assays indicated that ACTB was up-regulated4.4-fold in?fteen paired samples of ESCC and adjacent normal esophageal tissues[32].However,ACTB was down-regulated at the RNA level in esophageal carcinoma;mRNA levels of ACTB were decreased0.8-fold in esophageal carcinoma tissues in comparison with normal esophageal tissues[21].Thus ACTB is associated with the formation and malignancy of esophageal carcinomas,although the de-tailed action mechanism needs to be clari?ed.

2.7.ACTB is closely associated with lung cancer

As the leading cause of cancer-related deaths,lung cancer has an overall?ve year survival rate of~15%[16,33].Lung cancer is usually diagnosed in highly advanced stages,and frequently too late for sur-gical intervention.

ACTB was proved to be unsuitable for gene expression normaliza-tion for non-small cell lung cancer(NSCLC)specimens and NSCLC cell lines.ACTB mRNA levels were signi?cantly increased in NSCLC cell lines/tissues in comparison to normal ones[33,34].Moreover,immuno-histochemistry(HIC)and proteomics results have also indicated that ACTB protein levels are also signi?cantly up-regulated in NSCLC sam-ples compared to normal ones[35].Serial analysis of gene expression (SAGE)pro?les of?fteen malignant lung tumors and matched non-malignant parenchyma samples also indicated that ACTB levels are quite different between lung cancer and non-lung cancer tissues [36].Thus ACTB de-regulation might be associated with the formation and malignancy of lung cancer and the up-regulation of ACTB is possibly

a sign of lung cancer cellular tumourigenesis.

2.8.ACTB might promote breast cancer cell proliferation and tumor aggressiveness

Breast cancer(BC)ranks?rst in incidence among women,it affects more than one million women,accounting for more than400,000deaths annually[16].ACTB was found to be differentially expressed in BC and was associated with BC drug resistance.

First,ACTB was differentially expressed in BC and thus unsuitably utilized as a reference gene/protein.qRT-PCR analyses of ACTB levels in estrogen receptor positive(ER+)invasive BC(IBC),ER-IBC,normal breast tissue and ER+BC cell lines indicated that ACTB is unsuitable for qRT-PCR data normalization of normal and malignant human breast samples[37].ACTB and transferrin receptor(TFRC)was found to be the best combination for quanti?cation of urokinase plas-minogen activator in BC by qRT-PCR.The ACTB gene alone,however, is not suitable for quantifying gene expression in BC[38].These results were also con?rmed by the higher variability of ACTB across BC,which made it unsuitable as a single housekeeper control[39].Second,ACTB differential expression was associated with metastasis of BC.qRT-PCR analysis of ACTB expression in the four human BC lines MCF-10A, MCF-10T(MCF-10A transformed with H-ras),MCF-7(tumorigenic but nonmetastatic)and MDA-mb-231(metastatic)indicated that the highest expression level of ACTB was detected in MDA-mb-231[40],which impli-cated ACTB involvement in BC metastasis.In addition,the averaged tran-script level of ACTB was signi?cantly decreased in leucocytes from BC patients compared with K562cells and normal leucocytes[41].Third, ACTB was associated with drug-resistance of BC.ACTB protein levels were down-regulated fourfold in MDA7-transduced BC T47D cell lines in comparison with untransduced-T47D cells[30].The gene level expres-sion of ACTB was also signi?cantly decreased in MCF-7BC cells following treatment with salicylic acid(SA)or heat shock(HS)due to drug-induced cell apoptosis[42].Since ACTB might play an important role in drug-related apoptosis of BC cells,the detailed mechanism of action is worthy of clari?cation.

2.9.ACTB is associated with prostate cancer and ovarian cancer

Prostate cancer is a leading cause of cancer death in men.The early detection and timely treatment of organ-con?ned disease is key to reducing prostate cancer mortality[43].qRT-PCR analysis indi-cated that ACTB was more highly expressed in human formalin-?xed paraf?n-embedded(FFPE)prostate cancer tissues than in matched peritumoral normal tissues obtained by laser microdissection[43,44]. Since ACTB was de-regulated in prostate cancer,it is unsuitable for nor-malization purposes in gene pro?ling studies between normal and ma-lignant prostate tissues[44].

Ovarian cancer is the leading course of death from gynecological malignancy.Serous ovarian cancer accounts for approximately60–80%of ovarian cancers and has spread to extra-ovarian sites at the time of diagnosis for the majority of patients.The5-year survival rate of women diagnosed with ovarian cancer at early stages of the disease is~95%,but drops to less than30%when patients are diagnosed at late stages of the disease.Ovarian cancer survival rates have not im-proved in the past few decades[45].Recently,new potential predictive and prognostic molecular markers for ovarian cancer were targeted by a comparative genetic study.Interestingly,ACTB levels were found to be signi?cantly increased in specimens from serous ovarian cancers com-pared with normal ovarian epithelial tissues.ACTB is not suitable for use as a reference for gene expression normalization in serous ovarian cancer,but it might be involved in ovarian cancer and there is a need for further investigation of the expression levels and roles of ACTB in other sub-types of ovarian cancer[45].

2.10.ACTB is a potential indictor and therapeutic target for leukemia

B-cell chronic lymphocytic leukemia(B-CLL)has a highly hetero-geneous clinical course and is the most common form of adult leuke-mia.There is a pressing need for better prediction of individual clinical progression to enable the selection of optimal therapies and prognostic factors for B-CLL.ACTB was found to be an unsuitable ref-erence for quantitative polymerase chain reaction(qPCR)genetic

41

C.Guo et al./Clinica Chimica Acta417(2013)39–44

expression comparison in CD19+B cells from B-CLL patients’periph-eral blood[46].Using the qPCR technique,Gao et al.found that the DNA concentration and integrity of ACTB were higher in the plasma of acute leukemia patients compare to healthy persons,which sug-gests that this increase might be a potential indicator for acute leuke-mia[47].In addition,ACTB was up-regulated more than twofold in retinoid acid(RA)resistant human acute promyelocytic leukemia (APL)cell line NB4-R1following As4S4treatment for24h,indicating ACTB protein might have potential as a therapeutic target for drug re-sistance of leukemia[48].

2.11.ACTB is associated with drug-resistance of lymphoma

Bortezomib,a26S proteasome inhibitor,is one of the most promising molecular-targeted approaches for treatment of mantle cell lymphoma (MCL)with up to40%remission rate in relapsed MCL.ACTB levels were signi?cantly decreased in bortezomib-sensitive MCL cells Granta519, HBL-2,Jeko-1and Rec-1in comparison with bortezomib-resistant MCL cell NCEB-1following treatment with25nM bortezomib for up to4h [49],suggesting that ACTB plays a critical role in MCL and should be targeted for therapeutic treatment of MCL.

3.Potential mechanisms of action of ACTB in cancer

Several studies have suggested that ACTB polymerization and localization might promote cancer cell motility,invasiveness and metastasis[2,4,6,8–11].ACTB polymerization and ACTB cytoskeleton formation drives cell protrusions and cell motility,which indicates that over-expression of ACTB might also enhance cancer cell motility. ACTB mRNA was found to be localized in the protrusions of different types of cancer cells in which ACTB is actively polymerized,and this ability to localize mRNA was correlated with the ef?ciency of cell mo-tility.Accumulated localization of ACTB mRNA was proved to be asso-ciated with the metastatic potentials of cancer cells,as delocalization of ACTB mRNA from cell leading edges was followed by the loss of cell polarity and directional movement.ACTB expression was signi?cantly up-regulated in highly invasive variants of different tumor cell lines [4,6,8,11],con?rming involvement of ACTB in tumor metastasis.

The differential accumulation of ACTB mRNA in the perinucleus and at the cell leading edge might affect the metastatic capacities of cancer cells by affecting the polarity and plasticity of cancer cell motility.The relevance of the distribution of ACTB mRNA to cancer cell metastatic po-tential was explored by using rat adenocarcinoma MTLn3(high meta-static potential)and MTC(low metastatic potential)cell lines.ACTB mRNA was distributed in the perinuclear region and at the leading edge in MTC cells,but was only distributed at the perinuclear region of MTLn3cells.This difference makes MTLn3cells unpolarized with re-spect to all cell shape and motility criteria in cell culture and in their his-topathological organization in primary tumors,while MTC cells are polarized in all these respects.The increased plasticity of cell locomo-tion and invasiveness of MTLn3cells result from the failure of metastatic cells to localize ACTB mRNA properly,causing them to be less polarized

Table1

The associations of ATCB with cancers.

Tumor type Expression pattern Implication References

Hepatocellular carcinoma(HCC)Up-regulated in HCV-induced and HBV-induced HCC;overexpressed

in tumorous tissues of HCC with higher invasiveness and metastasis;

increased in Hepatoma Morris5123cells with increased state of

ACTB polymerization and in N1S1rat hepatoma.ACTB is closely associated with liver cancer growth

and metastasis.

[1,4,8,18–22]

Melanoma ACTB mRNA levels in invasive melanoma cell T1C3were twofold

higher than that in non-invasive melanoma cell1C8melanoma cells

derived from the same melanoma patient.ACTB is not a suitable reference gene/protein for melanoma cells from either the same patient or from heterogeneous cellular subpopulations of the same pathological origin.

[13]

Renal cell carcinoma(RCC)ACTB signi?cantly increased in ccRCC tissues;ACTB levels greatly

varied in RCC lines and were marginally higher in malignant renal

tissues versus normal kidney tissues.ACTB potentially promotes the development of

RCC.

[23,24]

Colorectal cancer(CRC)ACTB protein level was down-regulated fourfold in

MDA7-transduced CRC DLD-1cells compared to

untransduced-DLD-1cells;ACTB was not stably and reliably

expressed in colorectal tumors and matched normal specimens

ACTB is de-regulated and involved in CRC.[9,27–30]

Gastric cancer(GC)ACTB showed a1.4-fold expression increase in gastric carcinoma

tissues compared to normal tissues at the mRNA level;ACTB was

expressed more positively in GC tissues than in cancer cell lines

(SNU-216,SNU-638,SNU-719,AGS,MKN-28,KATOIII,AGS/SNU-638)

ACTB is associated with GC at the mRNA level[9,21,31]

Pancreatic cancer(PC)ACTB was up-regulated in PC at both RNA and protein levels.ACTB is involved in PC and unsuitable as a reference

gene/protein.

[21]

Esophageal cancer ACTB was up-regulated by4.4-fold in ESCC at the protein level,while

down-regulated at the RNA level by0.8-fold ACTB de-regulation is associated with lung cancer.

ACTB up-regulation might be a sign of lung cancer

cellular tumourigenesis.

[21,32]

Lung cancer ACTB was signi?cantly increased in NSCLC cell lines/NSCLC tissues at

mRNA and protein levels.

[34–37]

Breast cancer(BC)ACTB was highly expressed in metastatic MDA-mb-231BC cells;

ACTB was decreased in leucocytes of BC patients compared with

K562cells and normal leucocytes;ACTB protein level was

down-regulated fourfold in MDA7-transduced BC T47D cell lines

compared to T47D;ACTB was signi?cantly decreased in MCF-7BC

cells following treatment with salicylic acid or heat shock.ACTB de-regulation is associated with BC metasta-

sis and drug treatment effects on BC.

[30,38–42]

Prostate cancer ACTB was more highly expressed in prostate cancer tissue than

matched peritumoral normal tissues.

ACTB might promote prostate cancer.[43,44]

Ovarian cancer(OC)ACTB was signi?cantly increased in specimens from serous OC

compared with normal ovarian epithelial tissues.

ACTB might correlate with OC.[45]

Leukemia ACTB DNA concentrations and DNA integrity were higher in the

plasma of acute leukemia patients than that in healthy controls;

ACTB was up-regulated more than twofold in RA resistant human

APL cell line NB4-R1following treatment with As4S4’ACTB up-regulation correlates with leukemia and is associated with its drug resistance.

[46–48]

Lymphoma ACTB was signi?cantly decreased in bortezomib-sensitive MCL cell

lines Granta519,HBL-2,Jeko-1and Rec-1compared to

bortezomibresistant MCL cell line NCEB-1.ACTB might enhance drug resistance of lymphoma.[49]

42 C.Guo et al./Clinica Chimica Acta417(2013)39–44

and therefore more?exible in their direction of motility.These results may have prognostic value for predicting the metastatic potential of cancer cells and cancers[50].In addition,the increased expression and redistribution of ACTB to the tips of pseudopodia were associated with the motile ability and invasiveness of cancer https://www.wendangku.net/doc/ef4429617.html,paring to MDCK(Madin-Darby Canine Kidney epithelial cells)and MSV (Moloney sarcoma virus-transformed)-MDCK cells,the up-regulation and speci?c accumulation of ACTB in the pseudopodia drive the exten-sion of pseudopodia and regulate the invasive and metastatic abilities of MSV-MDCK-INV(invasive MSV-MDCK cells)[6].Clearly,the remolding of the ACTB cytoskeleton could contribute to tumor malignancy.At the very least,the dynamic actin polymerization and the cytoskeleton are involved in certain cancers[51–55].G-actin was found to be signi?-cantly decreased and F-actin was increased in three human colon adeno-carcinoma cell variants(EB3,3LNLN,5W)with high metastatic potential and invasiveness,supporting the idea that high levels of actin polymeri-zation are a prerequisite for pseudopod formation and necessary for in?l-tration of cancer cells into surrounding tissues[4,11].Loss of F-actin, poorly arranged ACTB skeleton organization,and the presence of F-actin aggregates correlated with increased metastatic potential of tumor cells[54].Another study revealed that ACTB polymerization or ACTB remodeling played a pivotal role in regulating the morphologic and phenotypic events of malignant cells[55].

Since ACTB appears to have several as yet poorly understood roles in carcinogenesis,ACTB polymerization,actin cytoskeleton formation and micro?lament actin remodeling could be potential targets for drug development for prevention and treatment of certain cancers, and studies of ACTB involvement in cancers will likely provide a new perspective on molecular mechanisms of cancer initiation and growth.

4.Conclusions

While ACTB has been widely used as a reference gene/protein for quantifying expression in cancers,many studies have found it to be de-regulated in liver,melanoma,renal,colorectal,gastric,pancreatic, esophageal,lung,breast,prostate,ovarian cancers,leukemia and lym-phoma as summarized in Table1.This de-regulation of ACTB expression in tumor tissues or cells suggests that1)caution should be shown in utilizing ACTB as a reference gene/protein even for comparable cells;

2)ACTB might be not be an accurate way to normalize different types of clinical samples;3)ACTB might be involved in the pathogenesis,in-vasiveness and metastasis of certain cancers;4)ACTB has potential as a biomarker and as a target for antisense gene therapy for certain types of cancer.Although ACTB is well known as a classical housekeep-ing gene,a better understanding of the roles of ACTB in cancers is likely to provide valuable insights into cancer development and progression. Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China(81050010;81171957;81272186)and the Key Laboratory of the Department of Education of Liaoning(LS2010050). References

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