The predominant CD44 splice variant in prostate cancer binds fibronectin, and calcitonin stimulates its expression.
BACKGROUND
Prostate cancer (PC) consistently overexpresses variant the (v) isoform of the cell adhesion protein CD44, and loses expression of the standard (s) isoform.


METHODS
We re-expressed CD44 full-length (exons 1-20) or standard (exons 1-5 + 16-20) or enforced stable RNAi against CD44v, and the examined functional effects on PC. The effect of stable knockout of calcitonin, a paracrine factor, or its receptor, on CD44 was assessed.


RESULTS
Re-expression of full-length CD44 or CD44s increased the total CD44 mRNA and CD44s protein while suppressing CD44v. These approaches, and RNAi to CD44v, decreased invasion. In adhesion assays, benign prostate cells bound mainly to hyaluronan, whereas PC lost affinity for hyaluronan but bound more strongly to fibronectin. Re-expressing CD44s restored predominant hyaluronan binding. Knockout of the calcitonin receptor in PC-3 derived cells caused marked loss of CD44v expression and reversion to CD44s expression.


CONCLUSIONS
Calcitonin influenced PC's balance between CD44s and CD44v. CD44v controlled invasiveness, altered ligand binding, and provides a target for therapeutic intervention.
Iczkowski
Kenneth A
KA
Department of Pathology, The University of Florida, Veterans Administration Medical Center, Gainesville, FL, USA. iczkoka@pathology.ufl.edu
Omara-Opyene
A Levi
AL
Shah
Girish V
GV
D017398:Alternative Splicing; D002116:Calcitonin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D005353:Fibronectins / Q000378:metabolism*; D020868:Gene Silencing; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D018003:Receptors, Calcitonin / Q000172:deficiency / Q000235:genetics
C497483:CD44 protein, human; D005353:Fibronectins; D018960:Hyaluronan Receptors; D020033:Protein Isoforms; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018003:Receptors, Calcitonin; D002116:Calcitonin