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TM4SF3 promotes esophageal carcinoma metastasis via upregulating ADAM12m expression

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Abstract

Esophageal cancer is characterized by rapid clinical progression and poor prognosis due to adjacent tissue invasion and distant organs metastasis at a very early stage. TM4SF3 (transmembrane 4 superfamily 3), a member of tetraspanin family, has been reported as a metastasis associated gene in many types of tumors. Herein, we described new properties of TM4SF3 in tumor metastasis, which suggested that this gene might be involved in esophageal carcinoma metastasis. Western blotting revealed that TM4SF3 was overexpressed in 57.1% (8/14) of esophageal carcinomas and esophageal carcinoma cell lines with high-invasive potential. Exogenous expression of TM4SF3 in two low-invasive esophageal carcinoma cell lines, KYSE150 and EC9706, significantly promoted cell migration and invasion. Upregulating TM4SF3 expression in EC9706 cells promoted xenograft tumor invading into surrounding tissues, enhanced lung metastasis, and shortened the lifespan of mice (median survival EC9706-TM4SF3 106.5 days versus EC9706-Vector 169.0 days, P < 0.0001) in a spontaneous metastasis model. Further studies demonstrated that ADAM12m was upregulated by TM4SF3 overexpression in vitro and in vivo. Abrogating up-expression of ADAM12m by siRNA significantly suppressed TM4SF3-mediated invasion. Together, these data from our studies indicated that overexpression of TM4SF3 in esophageal cancer conferred advantage to the invasion and metastasis of this destructive disease. Upregulated expression of ADAM12m by TM4SF3 might play a key role in TM4SF3-mediated invasion and metastasis. TM4SF3 and ADAM12m might be potential targets of esophageal carcinoma for anti-metastasis therapy.

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Abbreviations

ADAM12:

A disintegrin and metalloproteinase

EMT:

Epithelial-mesenchymal transition

HE:

Hematoxylin and eosin

MMP:

Metalloproteinase(s)

RNAi:

RNA interference

SiRNA:

Small interference RNA

TM4SF3:

Transmembrane 4 superfamily 3

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Acknowledgments

This work was supported by grants from the National key basic research program (NKBRP) (973 program) (No. 2002CB513106) and the National Natural Science Foundation (30570818 and 30600279).We thank Professor Mingrong Wang (Cancer Institute/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China) for the kind supply the EC9706 cell line and Dr. Shimada Y for the KYSE esophageal cancer cells (Kyoto University Graduate School of Medicine, Japan).

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Authors and Affiliations

  1. Department of Cell and Molecular Biology, Cancer Institute (Hospital), Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100021, People’s Republic of China

    Zhuan Zhou, Yu-Liang Ran, Hai Hu, Jian Pan, Zhi-Feng Li, Li-Zhao Chen, Li-Chao Sun, Liang Peng, Xi-Lu Zhao, Long Yu, Li-Xin Sun & Zhi-Hua Yang

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  1. Zhuan Zhou
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  2. Yu-Liang Ran
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Corresponding author

Correspondence to Zhi-Hua Yang.

Appendix

Appendix

Case no.

Age (year)

Gender

Grade

TNM Stage

1

48

M

G3

T3N0M0

2

58

F

G3

T2N0M0

3

51

M

G2

T4N1M0

4

52

M

G2

T3N0M1

5

63

M

G2

T3N1M0

6

55

M

G3

T3N1M0

7

61

M

G1

T2N0M0

8

62

M

G3

T2N0M0

9

66

M

G1

T3N1M)

10

62

F

G3

T3N1M0

11

68

M

G2

T2N0M0

12

59

M

G3

T3N1M0

13

62

M

G2

T3N2M0

14

67

M

G1

T3N1M0

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Zhou, Z., Ran, YL., Hu, H. et al. TM4SF3 promotes esophageal carcinoma metastasis via upregulating ADAM12m expression. Clin Exp Metastasis 25, 537–548 (2008). https://doi.org/10.1007/s10585-008-9168-0

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  • DOI: https://doi.org/10.1007/s10585-008-9168-0

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