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CD276

Official Full Name
CD276 molecule
Organism
Homo sapiens
GeneID
80381
Background
The protein encoded by this gene belongs to the immunoglobulin superfamily, and thought to participate in the regulation of T-cell-mediated immune response. Studies show that while the transcript of this gene is ubiquitously expressed in normal tissues and solid tumors, the protein is preferentially expressed only in tumor tissues. Additionally, it was observed that the 3' UTR of this transcript contains a target site for miR29 microRNA, and there is an inverse correlation between the expression of this protein and miR29 levels, suggesting regulation of expression of this gene product by miR29. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]
Synonyms
B7H3; B7-H3; B7RP-2; 4Ig-B7-H3;
Bio Chemical Class
Immunoglobulin
Protein Sequence
MLRRRGSPGMGVHVGAALGALWFCLTGALEVQVPEDPVVALVGTDATLCCSFSPEPGFSLAQLNLIWQLTDTKQLVHSFAEGQDQGSAYANRTALFPDLLAQGNASLRLQRVRVADEGSFTCFVSIRDFGSAAVSLQVAAPYSKPSMTLEPNKDLRPGDTVTITCSSYQGYPEAEVFWQDGQGVPLTGNVTTSQMANEQGLFDVHSILRVVLGANGTYSCLVRNPVLQQDAHSSVTITPQRSPTGAVEVQVPEDPVVALVGTDATLRCSFSPEPGFSLAQLNLIWQLTDTKQLVHSFTEGRDQGSAYANRTALFPDLLAQGNASLRLQRVRVADEGSFTCFVSIRDFGSAAVSLQVAAPYSKPSMTLEPNKDLRPGDTVTITCSSYRGYPEAEVFWQDGQGVPLTGNVTTSQMANEQGLFDVHSVLRVVLGANGTYSCLVRNPVLQQDAHGSVTITGQPMTFPPEALWVTVGLSVCLIALLVALAFVCWRKIKQSCEEENAGAEDQDGEGEGSKTALQPLKHSDSKEDDGQEIA
Open
Disease
Adrenal cancer, Brain cancer, Metastatic tumour, Myeloproliferative neoplasm, Prostate cancer, Solid tumour/cancer
Approved Drug
0
Clinical Trial Drug
11 +
Discontinued Drug
0

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Detailed Information

CD276, also known as B7-H3, is a gene belonging to the B7 family, which is part of the immunoglobulin superfamily (IgSF). This gene codes for a protein that is very important in controlling immunological responses, especially T-cell-mediated immune responses. Although the transcript of CD276 is generally expressed in solid tumors and normal tissues, tumor tissues show preferred expression for its protein product. The target location for miR29 microRNA is found in the 3' untranslated region (UTR) of the CD276 transcript according to research. A negative connection between miR29 levels and CD276 expression points to miR29 maybe controlling CD276 expression. There also exist many alternative splicing variants of the CD276 gene that produce distinct isoforms.

Gene Function and Mechanism

Mostly engaged in immune regulation, the CD276 gene is crucial in T-cell activation and immune evasion by tumor cells. Acting as a co-stimulating or co-inhibitory molecule in immune responses, CD276 is a member of the B7 family and comprises additional molecules like B7-1, B7-2, and PD-L1. In tumor immunology especially, the CD276 protein controls immune cell activity, hence preserving equilibrium in immunological responses.

By reducing natural killer (NK) cell-mediated cytotoxicity, CD276 could shield tumor cells and help to explain the immune escape systems of malignancies. For neuroblastoma cells among other possible markers for tumor identification, it has been noted. Additionally, CD276 is thought to be involved in transplant rejection and regulating lymphocyte activity in mucosal surfaces. Crucially, it could also provide the placenta and fetus immunologically friendly surroundings throughout pregnancy.

Structure of CD276

Transmembrane proteins of type I include CD276. Human CD276 is encoded by a gene found on chromosome 15q24; the protein has 534 amino acids. The extensive extracellular domain of CD276 is well-known for including IgV-like and IgC-like structures. Two major isoforms of CD276 exist depending on differences in the extracellular domain: the 2Ig-B7-H3 isoform (containing one pair of these domains) and the 4Ig-B7-H3 isoform (containing two pairs of IgV-like and IgC-like domains). The most often occurring type among humans is the 4Ig-B7-H3 isoform.

Expression and Role in Cancer

Although CD276 is slightly expressed in normal tissues like the liver, pancreas, kidney cortex, and salivary gland, it is very expressed in many different tumor tissues. Research on several cancer types—including non-small cell lung cancer, pancreatic cancer, primary liver cancer, colorectal cancer (CRC), breast cancer, prostate cancer, melanoma, and head and neck cancer—has shown that CD276 is overexpressed in many of them. Often linked to poor prognosis, shorter overall survival (OS), and progression-free survival (PFS) is its overexpression in the tumor microenvironment (TME).

The expression of CD276 in epithelial cells, fibroblasts, and tumor-associated stromal cells emphasizes even more its relevance in cancer biology. further underscores its importance in cancer biology. Moreover, CD276 expression has been linked to immune escape in tumors, enabling cancer cells to evade immune detection and elimination. This property qualifies CD276 as a possible target for immuno-oncology treatments.

Immunological and Non-immunological Roles of CD276

Considered a negative regulator of immunological reactions is CD276. By engaging with its receptor(s) and thereby altering many signaling pathways, it reduces the activation and proliferation of CD4+ and CD8+ T lymphocytes. Crucially for immune cell activation and anti-tumor immunity, it may also reduce the synthesis of cytokines including interleukin-2 (IL-2) and interferon-gamma (IFN-γ). CD276 therefore supports cancer growth and leads to tumor immune evasion.

Apart from its immune-modulating action, CD276 is involved in non-immune mechanisms vital for tumor development. These include encouraging tumor cell proliferation, epithelial-mesenchymal transition (EMT), migration, angiogenesis, resistance to chemotherapy and radiation, and metastases. Research has shown that CD276 triggers signaling pathways including the PI3K-AKT pathway, which controls several cellular functions including migration, invasion, and cancer cell metastases. Moreover, CD276 improves the release of vascular endothelial growth factor (VEGF), therefore promoting angiogenesis and helping tumor development.

Moreover, CD276 was demonstrated to affect cancer cells' metabolic reprogramming. In colorectal cancer (CRC), for example, CD276 controls the KIF15-activated ERK1/2 signaling pathway, hence fostering chemoresistance. It has also been linked to the control of glycolysis, which cancer cells' energy metabolism depends on. These results underline the complex function of CD276 in immunological and non-immune tumorigenic processes.

Therapeutic Potential and Clinical Applications

CD276 has become a potential therapeutic target given its major influence on immune control and cancer development. Monoclonal antibodies aiming at CD276 are under investigation in many continuous clinical studies to counteract their suppressive action on immune cells. By stopping CD276-mediated immune suppression, these treatments seek to boost anti-tumor immunity. Such strategies might enable the current cancer immunotherapies—including immune checkpoint inhibitors like anti-PD-1/PD-L1 antibodies—to be more effective.

Figure 1 describes the role of B7-H3 in promoting tumor growth and immune responses, highlighting its effects on ROS, HIF-1α, glycolysis, and various immunotherapy strategies targeting B7-H3, as well as the signaling pathways involved in T cell activation and RCC cell behavior.Figure 1. B7-H3 promotes tumor growth by increasing ROS and HIF-1α through Nrf2 suppression and reducing SOD1, SOD2, and PRX3, driving aerobic glycolysis in cancer cells. (Lin X, et al., 2024)

Apart from immune regulation, aiming for CD276 might also help to stop non-immunological mechanisms supporting tumor development like angiogenesis and metastases. Targeting CD276 in concert with other treatment approaches helps scientists hope to solve some of the problems related to tumor resistance and recurrence.

References:

  1. Lin X, Guan T, Xu Y, et al. Efficacy of the induced pluripotent stem cell derived and engineered CD276-targeted CAR-NK cells against human esophageal squamous cell carcinoma. Front Immunol. 2024 Mar 19;15:1337489.
  2. Zhou WT, Jin WL. B7-H3/CD276: An Emerging Cancer Immunotherapy. Front Immunol. 2021 Jul 19;12:701006.
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