Publication Date




Embargo Period


Degree Type


Degree Name

Doctor of Philosophy (PHD)


Cancer Biology (Medicine)

Date of Defense


First Committee Member

Bal L. Lokeshwar

Second Committee Member

Karoline Briegel

Third Committee Member

Guy A. Howard

Fourth Committee Member

Xiang-Xi Xu

Fifth Committee Member

Mark L. Gonzalgo


The atypical C-X-C chemokine receptor 7 (CXCR7) is implicated in supporting aggressive cancer phenotypes in several cancers including prostate cancer. However, the mechanisms driving overexpression of this receptor in cancer are poorly understood. The aim of this current study was to investigate the role of CXCR7 in the progression to lethal castration resistant prostate cancer (CRPC). CXCR7 expression was measured after androgen receptor (AR) signaling was modulated through androgen deprivation, siRNA-mediated depletion of AR or antiandrogen treatment. Chromatin immunoprecipitation (ChIP) assays were performed to investigate the interaction of AR with the CXCR7 promoter. Clustered regularly interspaced short palindromic repeats (CRISPR) - Cas9 technology was used to abrogate expression of CXCR7. Immunoblotting and real-time quantitative PCR were performed to analyze downstream signaling. Androgen deprivation or chemical inhibition of AR significantly increased CXCR7 expression in androgen-responsive prostate cancer cell lines. Depletion of AR by siRNA prevented androgen-mediated suppression of CXCR7, indicating this phenotype is dependent on AR. Increased CXCR7 expression during androgen deprivation facilitated enhanced epidermal growth factor receptor (EGFR)-mediated mitogenic signaling, promoting tumor cell survival through an androgen-independent signaling program. ChIP assays showed that AR binds to the CXCR7 promoter, demonstrating that AR directly down-regulates CXCR7 mRNA transcription, a suppressive mechanism which is disrupted when AR signaling is interrupted. CRISPR-Cas9-mediated knockout of CXCR7 revealed that prostate cancer cells depend on CXCR7 for proliferation, survival and clonogenic growth potential. Loss of CXCR7 expression by CRISPR-Cas9 gene editing resulted in the halt of cell proliferation, severely impaired EGFR signaling, and the onset of cellular senescence. LNCaP cells expressing a CRISPR-Cas9-derived CXCR7 mutant (characterized by a 392 nucleotide internal deletion, but maintaining the reading frame) remained proliferative in culture, but exhibited altered interactions between CXCR7 and scaffold protein and reduced mitogenic signaling potential. A xenograft study showed that the mutant line had substantially reduced tumorigenicity and growth rate relative to the wild-type (WT) LNCaP cell line. Together these results demonstrate that increased CXCR7 expression resulting from AR signaling inhibition drives EGFR-mediated, androgen-independent prostate cancer cell survival. Targeting CXCR7 expression as a combination treatment to androgen deprivation therapy may prevent androgen-independent growth and survival involved in therapeutic resistance and the progression to lethal CRPC.


CXCR7; prostate cancer; androgen receptor; CRISPR-Cas9; mitogenic signaling; senescence