Cancer cell-associated cytoplasmic B7-H4 is induced by hypoxia through hypoxia-inducible factor-1α and promotes cancer cell proliferation.
Aberrant B7-H4 expression in cancer tissues serves as a novel prognostic biomarker for poor survival in patients with cancer. However, the factor(s) that induce cancer cell-associated B7-H4 remain to be fully elucidated. We herein demonstrate that hypoxia upregulates B7-H4 transcription in primary CD138(+) multiple myeloma cells and cancer cell lines. In support of this finding, analysis of the Multiple Myeloma Genomics Portal (MMGP) data set revealed a positive correlation between the mRNA expression levels of B7-H4 and the endogenous hypoxia marker carbonic anhydrogenase 9. Hypoxia-induced B7-H4 expression was detected in the cytoplasm, but not in cancer cell membranes. Chromatin immunoprecipitation analysis demonstrated binding of hypoxia-inducible factor-1α (HIF-1α) to proximal hypoxia-response element (HRE) sites within the B7-H4 promoter. Knockdown of HIF-1α and pharmacological inhibition of HIF-1α diminished B7-H4 expression. Furthermore, knockdown of cytoplasmic B7-H4 in MCF-7 decreased the S-phase cell population under hypoxia. Finally, MMGP analysis revealed a positive correlation between the transcript levels of B7-H4 and proliferation-related genes including MKI67, CCNA1, and Myc in several patients with multiple myeloma. Our results provide insight into the mechanisms underlying B7-H4 upregulation and its role in cancer cell proliferation in a hypoxic tumor microenvironment.
Department of Microbiology and Immunology, Inje University College of Medicine, Busan 614-735, Republic of Korea; Advanced Research Center for Multiple Myeloma, Inje University College of Medicine, Busan 614-735, Republic of Korea.
You-Kyoung
YK
Jeon
Department of Microbiology and Immunology, Inje University College of Medicine, Busan 614-735, Republic of Korea.
Sae-Gwang
SG
Park
Department of Microbiology and Immunology, Inje University College of Medicine, Busan 614-735, Republic of Korea.
Il-Whan
IW
Choi
Advanced Research Center for Multiple Myeloma, Inje University College of Medicine, Busan 614-735, Republic of Korea.
Soo-Woong
SW
Lee
Department of Internal Medicine, Division of Hematology/Oncology, Busan Paik Hospital, Inje University, Busan 614-735, Republic of Korea.
Sang Min
SM
Lee
Department of Microbiology and Immunology, Inje University College of Medicine, Busan 614-735, Republic of Korea; Advanced Research Center for Multiple Myeloma, Inje University College of Medicine, Busan 614-735, Republic of Korea. Electronic address: miccih@inje.ac.kr.
Inhak
I
Choi
D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D047369:Chromatin Immunoprecipitation; D003593:Cytoplasm / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D061986:MCF-7 Cells; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D059016:Tumor Microenvironment / Q000235:genetics / Q000502:physiology; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011994:Recombinant Proteins; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1; C475826:VTCN1 protein, human
B7–H4; Hypoxia; Hypoxia-inducible factor-1α; Proliferation