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- Table of Contents
Facts about Annexin A6.
May associate with CD21.
May regulate the release of Ca(2+) from intracellular stores..
Human | |
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Gene Name: | ANXA6 |
Uniprot: | P08133 |
Entrez: | 309 |
Belongs to: |
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annexin family |
67 kDa calelectrin; Annexin A6; annexin VI (p68); Annexin VI; Annexin-6; ANX6; ANXA6; calcium-binding protein p68; Calelectrin; calphobindin II; calphobindin-II; CBP68; chromobindin-20; CPB-II ; CPB-II; Lipocortin VI; p68; p70; Protein III
Mass (kDA):
75.873 kDA
Human | |
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Location: | 5q33.1 |
Sequence: | 5; NC_000005.10 (151100706..151157779, complement) |
Cytoplasm. Melanosome. Identified by mass spectrometry in melanosome fractions from stage I to stage IV.
There are a number of benefits of the ANXA6 marker for immunotherapy and cancer research. It is a candidate protein to be used in antibody-mediated targeting PDAC. Furthermore, this protein is expressed in several aggressive cancers. It is therefore a 9E1 target antibody. Continue reading to learn more about ANXA6. In this article, we'll discuss the most useful uses of this biomarker.
Although the role played by ANXA6 in cancer remains unclear, there are some signs that it does. AnxA6 is a protein which regulates cell growth. However, when AnxA6 is downregulated, cancer cells exhibit anchorage-independent growth. This is why further research is needed in order to determine the role that this protein plays for cancer.
Interestingly, AnxA6 downregulation did not affect colony morphology despite a temporary decrease in expression. This suggests that AnxA6 is involved with internalization and trafficking activated receptors. AnxA6 knockdown results in cells with decreased motility. These results suggest that AnxA6 could play a role in inhibiting tumor growth and progression.
EGFR is found to be specific in cancer cell lines. EGFR is found in lipid rafts where it enhances gefitinib resistance. However, AnxA6 depleted cells were more sensitive to EGFR-targeted TKIs including lapatinib and PD153035.
Recent studies suggest that AnxA6 may be a marker of the prognosis or invasion stage of BC. AnxA6 expression was reduced by 60% in invasive ductal carcinoma, and by seventy percent for mucous adenocarcinoma. Proliferating cells were barely detectable in normal breast tissue. Moreover, anxA6-depleted cells were more responsive to EGFR-targeted tyrosine kinase inhibitors.
Recent studies have shown that AnxA6 plays a role in terminating the EGFR-mediated Ras signaling pathway. AnxA6 was found downregulated in BC cell lines with EGFR expression. AnxA6 overexpression reduced activation by the EGF-induced Ras pathway. It promoted Ca2+dependent membrane targeting and p120GAP.
AnxA6 inhibits EGFR activity, suggesting that it may play a role in tumour progression. Furthermore, AnxA6 overexpression inhibits anchorage-independent growth in MDA-MB-231 cells. It stabilizes activated cell membrane receptors, which leads to sustained signaling. Further studies are needed before AnxA6 can be confirmed as a tumour suppressor against cancer cells.
MAb 9E1 is a powerful anti-invasive agent against a variety aggressive cancers. This includes lung squamous cell carcinoma and colon adenocarcinoma. The immunoreactivity of this candidate proteins was low in normal tissues. However, it was significantly higher in tumours containing PNI. This is a strong predictor for poor prognosis. The immunoreactivity of 9E1 was weak in most normal tissues and vital organs, suggesting that it may have off-tumour toxicities.
In three clinical trials, the immunoreactivity of MAb 9E1 to AnxA6 against normal tissues and tumour cells was evaluated. Immunostaining tumor cells was assessed in semi-quantitative scoring systems based on the intensity and number stained tumour cells. After assessing the immunoreactivity, they determined whether anxA6 expression was associated with tumour budding or PNI. The study also showed that high AnxA6 expression was a weakly correlated predictor of disease-related outcomes in a cohort of 57 patients with PDAC.
A recent study showed that CAF-derived EVs contain a substance that regulates the communication between pancreatic cancer cells and stromal cells. These authors also confirmed that CAFs contained annexinA6, which promotes pancreatic cancer's aggressiveness. Moreover, they showed that thrombospondin 1 is expressed by CAFs, a sign of its enriched CAFs.
ANXA6's anti-tumor activity is not the only important function. There is an active STAT3 pathway that is present in PDAC cells and ANXA6 plays an important role in regulating immune system. STAT3 signals promote MDSC differentiation and T regulatory cell proliferation. Additionally, high levels of TGFb signaling in PDAC cells decreases NK cell activation and boosts the differentiation of T regulatory cells.
Although the role for AnxA6 in pancreatic tumors is not known, it has been implicated with invasion and migration. AnxA6 immune response has been shown to be associated in normal pancreas islet cells. Studies have also shown that the development of PDAC tumors is associated with pERK activity as well as LGR5 expression. Multiple animal models have shown that AnxA6 silencing can reduce invasiveness.
The ANXA6 mutation is a tumor suppressor gene in skin cancer. This is a common type of melanoma. It has been associated to decreased expression of B16F1O melanoma when compared to syngeneic, immortalized melanocyte cells. Additionally, melanoma progression was inversely related to AnxA6 protein levels. Immunohistochemical tests revealed decreased expression and increased tumor malignancy. This suggests that AnxA6 could be responsible for slowing down the progression to melanoma.
Lomnytska (et al.) found that AnxA6 expression was more prominent in the cytoplasm than cell membranes from SCC and SCE cells. AnxA6 cytoplasmic expression was also observed increasing with the progression from microinvasive to more invasive SCC. Additionally, invasive SCC had the highest sensitivity/specificity and microinvasive cancer had the lowest levels of AnxA6.
The ANXA6 Gene is highly expressed by a number of aggressive types of cancer, including lung squamous. Colon adenocarcinoma. TNBC and HER-2 positive breast carcinoma. These cancers may have high levels of AnxA6 expression. However, this could be due to other toxicities. However, a high level of AnxA6 expression in tumour cells doesn't necessarily indicate that the disease is aggressive.
AnxA6 expression was also associated with tumour growth in breast and gastric cancer cell lines. AnxA6's reduced expression supports its role in breast cancer suppression. It also inhibits the motility of breast cancer cells and their invasiveness, which is consistent with its role as a tumour suppressor. PDAC also shows that anxA6 does not correlate to lymphovascular invasion and age.
The ANXA6 gene is composed of 26 exons and is found on chromosome 5q32-q34. AnxA6 includes two annexindomains. These domains might have been formed from fusion duplications in the ANXA5/ANXA10 genomes. AnxA6 activation occurs through the presence of two annexindomains. These domains harbor Ca 2+ binding locations and putatively phosphorylation site located at Ser13 Ty30 and Thr356.
Researchers have found high levels of this candidate proteins in many cancer subtypes using a monoclonal anti-ANXA6 antibody. They also discovered that 9E1 was weakly immunoreactive in normal tissues despite being highly expressed in cancer. They also found that 9E1 was capable of inhibiting MMP-9 expression in MDAMB-231 cells.
The team created monoclonal antibodies against AnxA6 using a highly invasive cell line and tested their antiinvasive activity against aggressive cancer cells in vitro. Using immunoprecipitation/liquid chromatography-tandem mass spectrometry, the antibody was identified as an inhibitory MAb against 9E1 target antigen. They then tested MAb 9E1 in vitro for its anti-tumour effect and in immunohistochemical analyses of tumour-associated 9E1 Target Antigen expression in normal and malignant tissues.
AnxA6 is expressed on a cell surface as a receptor for Fetuin-A and chondroitin sulfate. Therefore, the anti-Fetuin-A and 9E1 monoclonal antibodies have potential as potential anti-cancer drugs. They could also be useful in the treatment of other types. Monoclonal antibodies against 9E1 are highly specific for cancer cells. However their anti-invasive properties make them a great candidate for cancer immunotherapy.
AnxA6 has been shown to be involved in tumour growth. It inhibits motility and invasiveness cell lines for breast and gastric tumors. A siRNA-mediated knockdown reduces tumour growth in both breast and gastric. It acts as a tumor suppressor. AnxA6 expression in cancer cells is related to tumour progression but is not directly linked to cancer growth.
PMID: 3258820 by Crompton M.R., et al. Primary structure of the human, membrane-associated Ca2+-binding protein p68 a novel member of a protein family.
PMID: 2963335 by Suedhof T.C., et al. Human 67-kDa calelectrin contains a duplication of four repeats found in 35-kDa lipocortins.