Frequent deletion of 3p21.1 region carrying semaphorin 3G and aberrant expression of the genes participating in semaphorin signaling in the epithelioid type of malignant mesothelioma cells

Our plain-English summary of Frequent deletion of 3p21.1 region carrying semaphorin 3G and aberrant expression of the genes participating in semaphorin signaling in the epithelioid type of malignant mesothelioma cells, by Y. Yoshikawa, A. Sato, T. Tsujimura, et al (International Journal of Oncology, 2011).

The study

• Authors: Y. Yoshikawa, A. Sato, T. Tsujimura, T. Morinaga, K. Fukuoka, S. Yamada, A. Murakami, N. Kondo, S. Matsumoto, Y. Okumura, F. Tanaka, S. Hasegawa, T. Hashimoto-Tamaoki, T. Nakano
• Journal: International Journal of Oncology
• Published: 2011;39(6):1365-74
• Cited by: 22 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Array-based comparative genomic hybridization analysis was performed on 21 malignant mesothelioma (MM) samples (16 primary cell cultures and 5 cell lines) and two reactive mesothelial hyperplasia (RM) primary cell cultures. The RM samples did not have any genomic losses or gains. In MM samples, deletions in 1p, 3p21, 4q, 9p21, 16p13 and 22q were detected frequently. We focused on 3p21 because this deletion was specific to the epithelioid type. Especially, a deletion in 3p21.1 region carrying seven genes including SEMA3G was found in 52% of MM samples (11 of 14 epithelioid samples). The allele loss of 3p21.1 might be a good marker for the epithelioid MM. A homozygous deletion in this region was detected in two MM primary cell cultures. A heterozygous deletion detected in nine samples contained the 3p21.1 region and 3p21.31 one carrying the candidate tumor suppressor genes such as semaphorin 3F (SEMA3F), SEMA3B and Ras association (RalGDS/AF-6) domain family member 1 (RASSF1A). SEMA3B, 3F and 3G are class 3 semaphorins and inhibit growth by competing with vascular endothelial growth factor (VEGF) through binding to neuropilin. All MM samples downregulated the expression of more than one gene for SEMA3B, 3F and 3G when compared with Met5a, a normal pleura-derived cell line. Moreover, in 12 of 14 epithelioid MM samples the expression level of SEMA3A was lower than that in Met5a and the two RM samples. An augmented expression of VEGFA was detected in half of the MM samples. The expression ratio of VEGFA/SEMA3A was significantly higher in the epithelioid MMs than in Met5a, RMs and the non-epithelioid MMs. Our data suggest that the downregulated expression of SEMA3A and several SEMA3s results in a loss of inhibitory activities in tumor angiogenesis and tumor growth of VEGFA; therefore, it may play an important role on the pathogenesis of the epithelioid type of MM.

In plain English

This Japanese laboratory study looked for genetic changes in malignant mesothelioma cells. The authors analyzed 21 mesothelioma samples (16 primary cell cultures and 5 cell lines), two reactive mesothelial hyperplasia cultures, which they grouped as non-malignant, and two tumor specimens. The article does not report patients' asbestos exposure. The hyperplasia samples showed no obvious genetic losses or gains. All 21 mesothelioma cell samples had homozygous deletions (both copies lost) in the 9p21 region. Losses of the 3p21.1 region on chromosome 3 were found only in epithelioid samples. One biphasic sample had a one-copy loss extending into 3p21.31, but that loss did not include the SEMA3B and SEMA3F genes. Two cultures had lost both copies of 3p21.1, which carries SEMA3G, and 9 of 14 epithelioid samples had lost one copy. SEMA3A expression was significantly lower in epithelioid samples than in hyperplasia samples (p=0.02). The VEGFA/SEMA3A expression ratio was significantly higher in epithelioid samples than in hyperplasia and non-epithelioid samples (p less than 0.01 each). The authors concluded that 3p21.1 loss and a high VEGFA/SEMA3A ratio might be good markers of epithelioid mesothelioma.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory genetic study: copy-number analysis by array-based comparative genomic hybridization (CGH), plus gene expression analysis by microarray and real-time PCR, on cultured cells and tumor specimens
• Who was studied: 21 malignant mesothelioma cell samples (16 primary cell cultures and 5 cell lines), 2 reactive mesothelial hyperplasia primary cell cultures, 2 tumor specimens, and the Met5a normal pleura-derived cell line as reference. Patient material came from 18 mesothelioma patients at the Hospital of Hyogo College of Medicine, Japan. Of the mesothelioma samples, 14 were epithelioid and 7 non-epithelioid. Dates are not given.
• Exposure: Asbestos exposure was not assessed. The study measured gene deletions and gene expression in mesothelioma cells.
• Main results:
  • The two reactive mesothelial hyperplasia samples showed no obvious genomic imbalance
  • All mesothelioma cell samples had homozygous deletions in the 9p21 region
  • Deletions in the 22q region carrying the NF2 gene were found at a frequency of 62% in mesothelioma samples of all histological types
  • The authors reported the 3p21 deletion as specific to epithelioid mesothelioma; two primary cell cultures had a homozygous deletion (both copies lost) in the 3p21.1 region
  • Table I notes that the biphasic sample MM16-P had a one-copy loss from 3p22.1 into 3p21.31; the deleted interval did not include SEMA3B and SEMA3F
  • 9 of the 14 epithelioid mesothelioma samples had a heterozygous deletion (one copy lost) of 3p21 covering both 3p21.31, which carries SEMA3B, SEMA3F and RASSF1A, and 3p21.1
  • SEMA3G expression was detected in Met5a but lost in many mesothelioma samples. The exceptions were five epithelioid samples (MM19-P, MM45-P, H28, H2452 and HMMME) and two non-epithelioid samples (MM16-P and MM30-P).
  • SEMA3B and SEMA3F expression was frequently downregulated in mesothelioma samples (81% and 62%, respectively)
  • SEMA3A expression in epithelioid mesothelioma samples was significantly lower than in the reactive hyperplasia samples (p=0.02)
  • VEGFA expression was more than 2-fold higher than in Met5a in 7 of 14 epithelioid and 4 of 7 non-epithelioid mesothelioma samples
  • The difference in VEGFA expression between epithelioid and non-epithelioid mesothelioma was not statistically significant
  • The VEGFA/SEMA3A expression ratio in epithelioid mesothelioma samples was significantly higher than in reactive hyperplasia samples and in non-epithelioid mesothelioma samples (p less than 0.01 for each)
  • All mesothelioma samples lost expression of more than one NRP1 or NRP2 agonist; in the two reactive hyperplasia samples, SEMA3G was the only class 3 semaphorin whose expression was lost
• The authors' conclusion: The authors concluded that loss of the 3p21.1 region and a high VEGFA/SEMA3A expression ratio might be good markers of the epithelioid type of mesothelioma
• Limitations the authors state:
  • The authors stated that further analysis is needed to identify other tumor suppressor genes in the 3p21.1 region
  • The authors stated that how loss of SEMA3G expression contributes to mesothelioma is not clear
  • SEMA3G expression was low in cultured cells and gave a low signal-to-noise level on microarray

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Epithelioid, Mesothelioma, Reactive Mesothelial Hyperplasia, Homozygous Deletion, Tumor Suppressor Gene, Pleura, Non-epithelioid, Angiogenesis.

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