Aberrations of a cell adhesion molecule CADM4 in renal clear cell carcinoma

Abstract

Renal clear cell carcinoma (RCCC) is the most frequent subpopulation of renal cell carcinoma and is derived from the proximal uriniferous tubules. We have previously reported that an actin‐binding protein, 4.1B/DAL‐1, is expressed in renal proximal tubules, whereas it is inactivated in 45% of RCCC by promoter methylation. In the lung and several epithelial tissues, 4.1B is shown to associate with a tumor suppressor protein, CADM1, belonging to the immunoglobulin‐superfamily cell adhesion molecules. Here, we demonstrate by immunohistochemistry that another member of the CADM‐family protein, CADM4, as well as 4.1B is expressed specifically in human proximal tubules, while CADM1 and 4.1N, another member of the 4.1 proteins, are expressed in the distal tubules. Immunoprecipitation analysis coupled with Western blotting revealed that CADM4 associated with 4.1B, while CADM1 associated with 4.1N in the lysate from normal human kidney, implicating that a cascade of CADM4 and 4.1B plays an important role in normal cell adhesion of the proximal tubules. On the other hand, CADM4 expression was lost or markedly reduced in 7 of 10 (70%) RCC cell lines and 28 of 40 (70%) surgically resected RCCC, including 10 of 16 (63%) tumors with T1a. CADM4 expression was more preferentially lost in RCCC with vascular infiltration (p = 0.04), suggesting that loss of CADM4 is involved in tumor invasion. Finally, introduction of CADM4 into an RCC cell line, 786‐O, dramatically suppressed tumor formation in nude mice. These findings suggest that CADM4 is a novel tumor suppressor candidate in RCCC acting with its binding partner 4.1B.

Decreased expression of CADM1 and CADM4 are associated with advanced stage breast cancer

“…The aforementioned breast cancer tissue samples were fixed in 10% formalin, embedded in paraffin, cut into 4 µm sections and stained with hematoxylin and eosin (H&E) and other primary antibodies. Rabbit polyclonal antibodies against CADM1 (1:500, C-18, generated by the Division of Molecular Pathology, Institute of Medical Science, The University of Tokyo) and CADM4 (1:500, Bc-2, generated by the Division of Molecular Pathology, Institute of Medical Science, The University of Tokyo) were used as described previously (20). Antibodies used for IHC staining were as follows: Anti-ER (1:500, cat.…”

Clinicopathological significance of CADM4 expression in invasive ductal carcinoma of the breast

“…To date, reduced expression and loss of CAMD4 has been studied in glioma, prostatic, renal and colon cancers 5 6 8 16. The correlation between CADM4 expression and clinicopathological factors has been investigated only in two cancers: renal cell carcinoma and colorectal adenocarcinoma 8 16.…”

“…The correlation between CADM4 expression and clinicopathological factors has been investigated only in two cancers: renal cell carcinoma and colorectal adenocarcinoma 8 16. Nagata et al 16 suggested that promoter methylation was involved in the silencing of CADM4 in renal cell carcinoma (human renal cancer 786-O cells). They demonstrated that loss of CADM4 expression occurred more frequently in renal cell carcinoma with vascular invasion than without it (p=0.04), which indicated a relationship between CADM4 and tumour invasiveness.…”

Clinicopathological significance of CADM4 expression, and its correlation with expression of E-cadherin and Ki-67 in colorectal adenocarcinomas

“…Nagata et al 14 obtained evidence that promoter methylation is involved in the silencing of CADM4. When they treated human renal cancer 786-O cells (in which CADM4 expression is undetectable) with methyl transferase, they found that synthesis of CADM4 mRNA was restored.…”