Quantitative evaluation of the apoptosis regulating genes Survivin, Bcl-2 and Bax in inflammatory and malignant pleural lesions.
OBJECTIVE
We aimed to identify defects in the programmed cell death pathway that can be related to pleural malignant mesothelioma (MM) unresponsiveness to chemotherapy.


METHODS
We quantified mRNA levels of the apoptosis regulating genes Survivin, member of the IAP family, Bcl-2 and Bax, members of the Bcl-2 family. We studied 22 non-neoplastic pleural samples, comprising normal and inflammatory tissue specimens, and 42 pleural MMs using real-time RT-PCR.


RESULTS
Very low mRNA levels of each apoptotic gene were detected in all normal pleural samples. All three genes displayed increased mRNA levels in inflammatory and tumor specimens. Survivin levels in pleuritis and MMs were significantly increased (333% and 908%, respectively) compared to normal counterparts (p=0.0147 and 0.00349, respectively). Bcl-2 and Bax levels were increased in inflammatory pleural samples (394%, p=0.001 and 188%, p=ns, respectively) and in MMs (94%, p=ns and 88%, p=0.0163, respectively). The Bcl-2/Bax ratio was higher in pleuritis than in MMs, compared to normal pleurae (441%, p=ns and 22%, p=ns, respectively); the difference between Bcl-2/Bax ratio in inflammatory and neoplastic pleural samples was significant (p=0.00375).


CONCLUSIONS
These results suggest that apoptotic defects in pleural MMs are linked to increased levels of Survivin, whereas variations in Bcl-2 and Bax expression appear less significant, although further studies are needed to highlight Bcl-2 family members interactions in apoptosis control. Survivin progressive accumulation from normal pleura to MM suggests this gene may be important in mesothelial cancerogenesis. Survivin overexpression may also be involved in pleural MM resistance to oncological therapies. Therefore, Survivin may represent a promising novel target for selective therapies.
Falleni
Monica
M
Department of Medicine Surgery and Dentistry, Division of Pathology, University of Milan, AO San Paolo e IRCCS Ospedale Maggiore, Via A. Di Rudinì 8, 20142 Milan, Italy. monica.falleni@unimi.it
Pellegrini
Caterina
C
Marchetti
Antonio
A
Roncalli
Massimo
M
Nosotti
Mario
M
Palleschi
Alessandro
A
Santambrogio
Luigi
L
Coggi
Guido
G
Bosari
Silvano
S
D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics*; D016022:Case-Control Studies; D002471:Cell Transformation, Neoplastic; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D019254:Genes, bcl-2; D006801:Humans; D007249:Inflammation; D051034:Inhibitor of Apoptosis Proteins; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology*; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009363:Neoplasm Proteins; D010995:Pleural Diseases / Q000235:genetics / Q000503:physiopathology; D010997:Pleural Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077022:Survivin; D051028:bcl-2-Associated X Protein
D000970:Antineoplastic Agents; C494826:BAX protein, human; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D000077022:Survivin; D051028:bcl-2-Associated X Protein