Immunolocalization of the Tumor-Sensitive Calmodulin-Like Protein CALML3 in Normal Human Skin and Hyperproliferative Skin Disorders

Abstract

Background and ObjectiveCalmodulin-like protein CALML3 is an epithelial-specific protein regulated during keratinocyte differentiation in vitro. CALML3 expression is downregulated in breast cancers and transformed cell lines making it an attractive marker for tumor formation. The objective of this study was to survey CALML3 localization in normal epidermis and in hyperproliferative skin diseases including actinic keratosis, squamous and basal cell carcinoma as well as verruca and psoriasis and to compare CALML3 immunoreactivity with the proliferation marker Ki-67.MethodsParaffin-embedded tissue sections from normal human skin and hyperproliferative skin disorders were examined by immunohistochemistry and analyzed for localization and expression of CALML3 and Ki-67.ResultsCALML3 was strongly expressed in differentiating layers of normal skin, staining the periphery in suprabasal cells and exhibiting nuclear localization in the stratum granulosum. CALML3 nuclear localization was inversely correlated to Ki-67 staining in each disease, indicating that CALML3 nuclear presence is related to terminal cell differentiation and postmitotic state.ConclusionsIncreased CALML3 expression in suprabasal layers is characteristic for differentiating keratinocytes in normal epidermis, and nuclear expression of CALML3 inversely correlates with expression of the proliferation marker Ki-67. This suggests that CALML3 is a useful marker for normal and benign hyperplastic epidermal development, whereas the loss of nuclear CALML3 indicates progression to a proliferative and potentially malignant phenotype.

Defining the actinic keratosis field: a literature review and discussion

“…Twenty‐nine studies provided molecular/genetic/immunological evidence relevant to inform a field definition in AK (Table ) …”

Integration of transcriptome and methylome analysis of aldosterone-producing adenomas

“…CALML3, an epithelial-specific calcium-sensing protein, has also been identified as being an up-regulated and promoter-hypomethylated gene. CALML3, which is expressed at high levels in normal epithelium, has also been shown to be down-regulated during malignant transformation, and it thus assumed to be a biomarker of terminally differentiated epithelium (38,39). It has been shown that specific DNA hypomethylation at gene promoter regions plays a crucial role in tumorigenesis through the up-regulation of oncogenes, such as Rras in gastric cancer and cyclin D2 in pancreatic cancer (44).…”

“…PRRX1 (31, 32), RAB38 (33), FAP (34, 35), GCNT2 (36), and ASB4 (37) have been associated with tumor progression. By contrast, CALML3 has been documented as a marker in well-differentiated tissues (38,39).…”

UVB induces apoptosis via downregulation of CALML3-dependent JNK1/2 and ERK1/2 pathways in cataract

“…Notably, overexpression of CALML3 in HLECs significantly reduced apoptosis, ROS production and intracellular Ca 2+ concentration following exposure of HLECs with 2 W/m 2 UVB irradiation for 90 min. Similar to the ubiquitous Ca 2+ sensor protein calmodulin, CALML3 acts in pre-apoptotic cells by interacting with a nuclear protein involved in chromosome fragmentation (20). The findings of the current study suggest that UVB irradiation induces apoptosis by downregulating expression of CALML3, and upregulation of CALML3 can reverse the UVB-induced damage of HLECs.…”

“…Ca 2+ is also involved in cell growth, differentiation and motility during the transformation and progression of cancer. Calmodulin like 3 (CALML3) is an epithelial-specific calcium sensing protein that highly expressed in oral mucosa, skin, breast and prostate (19,20). A previous study reported that CALML3 is regulated by short-term blockade of the MaxiK channel associated with an increase in basal Ca 2+ concentration (21).…”