Upregulation of CRMP4, a new prostate cancer metastasis suppressor gene, inhibits tumor growth in a nude mouse intratibial injection model

Abstract

Prostate cancer, the most commonly diagnosed male cancer in North America, has a high incidence of bone metastasis. Our previous study showed collapsin response mediator protein 4 (CRMP4) gene inhibited prostate cancer migration and invasion. In this study, we investigated whether overexpression of CRMP4 gene in prostate cancer cells inhibit tumor bone metastasis. The stable prostate cancer cells overexpressing the CRMP4 gene were constructed using lentivirus infection. Prostate cancer bone metastasis nude mouse model was built though orthotopic prostate implantation, intracardiac injection and intratibial injection with CRMP4 overexpress and control cancer cells. Small animal PET/CT scanning results showed no difference of bone metastatic capacity in orthotopic and intracardiac injection models between CRMP4 overexpression and control group, while CRMP4 overexpression inhibited tumor growth in the intratibial injection model. Moreover, our in vitro study showed CRMP4 overexpression downregulates the Neuropilin1 (NRP1) expression and upregulate the Noggin expression. Immunohistochemical staining of the hind limbs of intratibial injection model was confirmed with cytological experiments. Taken together, our research indicated CRMP4 inhibits prostate cancer cells growth in the nude mouse bone microenvironment and this effect may relate with regulation of NRP1 and Noggin expression.

Collapsin response mediator protein 4 isoforms (CRMP4a and CRMP4b) have opposite effects on cell proliferation, migration, and invasion in gastric cancer

“…We found that CRMP4a overexpression and CRMP4b silencing suppressed gastric carcinoma cell proliferation, migration, cell cycle progression, invasion, and adhesion, but did not affect apoptosis. These results differ from those of prior studies on prostate and pancreatic cancer: CRMP4 had no effect on cell proliferation in either of these cancers [ 20 , 22 ]. Consistent with the results of previous studies on prostate and pancreatic cancer, we found that CRMP4a and CRMP4b play an important role in regulating cell migration and invasion.…”

“…Furthermore, CRMP4a (TUC-4a) and CRMP4b (TUC-4b) exhibit opposing functions in neurite outgrowth [ 6 , 19 ]. In addition, altered CRMP4 expression has been observed in several malignant tumors, including prostate cancer, pancreatic cancer, and neuroblastoma [ 14 , 20 – 22 ]. In prostate cancer, CRMP4 expression was inversely associated with lymph node metastasis [ 14 ].…”

CRMP4a suppresses cell motility by sequestering RhoA activity in prostate cancer cells

“…Our studies demonstrated that expression of CRMP4a, the shorter splicing variant, is significantly lower in metastatic prostate cancers than that in primary cancers at the mRNA and protein levels and that CRMP4a overexpression drastically suppressed cell migration and tumor metastasis in prostate cancer models 8 . Additionally, using the small activating RNA (saRNA) technique, we demonstrated that enhancement of CRMP4a expression completely blocked distant metastases in mouse xenograft models of prostate cancer 9 , which has been supported by others utilizing different approaches 10,11 .…”

Targeting CRMP-4 by lentivirus-mediated RNA interference inhibits SW480 cell proliferation and colorectal cancer growth

“…As a member of the CRMP family of cytosolic phosphoproteins, CRMP-4 serves a crucial function in the mediation of semaphorin/collapsin-induced growth cone collapse and regulating the neuronal development and myelin-dependent axon outgrowth ( 20 ). Differential expression of CRMP-4 has been observed in numerous types of malignancy ( 21 , 22 ). For example, CRMP-4 was differentially expressed in pancreatic cancer tissues and CRMP-4 silencing reduced cellular invasion, which indicates that CRMP-4 is significantly associated with poor prognosis by promoting liver metastasis and may serve as a novel therapeutic target for pancreatic cancer ( 15 ).…”