Recent Advances in Androgen-Receptor Splicing Variants Related to the Mechanism and Treatment of Castration-Resistant Prostate Cancer

 whp189@189.cn This article is published under the terms of the Creative Commons Attribution License 4.0 Author(s) retain the copyright of this article. Publication rights with Alkhaer Publications. Published at: http://www.ijsciences.com/pub/issue/2020-04/ DOI: 10.18483/ijSci.2303; Online ISSN: 2305-3925; Print ISSN: 2410-4477 Recent Advances in Androgen-Receptor Splicing Variants Related to the Mechanism and Treatment of Castration-Resistant Prostate Cancer Jianguo Liao, Wenhai Pan


Diagnostic Criteria of CRPC
In the definition of CRPC, "castration" includes surgical castration and drug castration. Regardless of the castration mode, 95% of the androgens will be removed in the future from the hypothalamic-pituitary-gonadal axis. Diagnosis of CRPC in the 2017 edition of the European Association of Urology (EAU) guidelines includes three criteria: (1) Serum testosterone reaching castration level (< 50 ng/dI, or < 1.7 nmol/L); (2)Prostate-specific antigen(PSA) progress: 3 times in a row during the interval of 1 week, the PSA increased by more than 50% from the minimum value, and the absolute value of PSA increase was >2 ng/mI. ; (3)Imaging progress: bone scan found two or more bone metastatic lesions or large soft tissue lesions meeting Response Evaluation Criteria in Solid Tumors .

2..2 Androgen Receptor (AR) and Androgen Receptor splicing Variant (AR-Vs)
Androgen receptor (AR) is a member of the steroid hormone receptor family.
[11] It contains n-terminal trans-activation domain (encoded by exon 1), DNA binding domain (encoded by exon 2 and 3), short hinge region (encoded by exon 4), and c-terminal ligand-binding domain (LBD; Exon 4-8 encoding), [12]AR is activated by binding to androgen, and plays a key role in male physiology and pathology, involved in all stages of prostatic tumor initiation, development, and therapeutic resistance.
[10] Prostate cancer by a variety of mechanisms such as AR gene amplification, mutation and steroid metabolism, cell signal transduction and regulation of the change of the core protein produces resistance to androgen deprivation therapy (ADT).
[13] The expression of androgen receptor splicing variants (AR -VS)lacking ligand-binding domain is a kind of new mechanism. [7] The discovery of the constitutive active AR splicing variant has become a new clinical trial and novel method for targeting AR. [13] As a truncated subtype of AR, the androgen-receptor splicer variant (AR-Vs) lacks ligand-binding domain and still has constitutive activity in the absence of circulating androgens. [

Androgen receptor Splicing Variant 7(AR-V7)
Ar-v7 /AR3 is one of the major splicing variants expressed in castration-resistant prostate cancer tissues in humans. It has constitutive activity and its transcriptional activity is not regulated by androgens or antiandrogens. During the progression of PCa, especially in hormone-refractory prostate cancer (HRPC), AR-V7 was significantly up-regulated and predicted biochemical recurrence after surgical treatment (P = 0.012). [31][23][27] The increased expression of AR-Vs (AR-V1, AR-V7 and AR-V567es) in bone metastasis in CRPC not only indicates the correlation with advanced bone metastasis of prostate cancer, but also indicates a very poorprognosis.[19]

AR-V7 is related to taxane chemotherapy in castration-resistant prostate cancer
Although AR-V7 expression of Circulating Tumor Cells (CTC) in metastatic castration-resistant prostate cancer(mCRPC) was not associated with major resistance to taxane chemotherapy, [35] it was shown in 37 metastatic CRPC patients treated with taxane (docetaxel or cabataxel) and 62 CRRP patients treated with enzalutamide or abirirone: In the AR-V7 negative patients, there was no difference in the outcomes of the three treatments, while in the AR-V7positive patients, the PSA response rate,PSA PFS and PFS of the taxanes treatment group were all higher than that of the enzalurudine treatment group or the abiraterone treatment group,with Prostate-specific antigen responses (41% vs 0%, P <.001), PSA PFS hazard ratio [HR] 0.19 [95%ci, 0.07-0.52] P = 0.001,PFS HR 0.21 [95%ci, 0.07-0.59], P = 0.003), [35] when positiveAR-V7 was detected in circulating tumor cells (CTCS) before treatment, the risk of death of choosing taxanes was lower than that of using androgen receptor signaling (ARS) inhibitors (HR, 0.24; 95% CI, 0.10-0.57; P = 0.035).
[29] In summary, the clinical outcome of taxanes was better than that of enzalutamide or abirirone, and AR-V7detection could be used as a treatment biomarker in CRPC. [35] AR-v7 is also a dynamic marker in abiritron, enzalutamide endocrine therapy, or taxane chemotherapy. "AR-V7can be transformed into a positive or negative state", and the continuous AR-V7 test in blood provides a method to observe the evolution of tumors in real time. [33]

Mechanism of AR-V7 induced castration resistance in CRRP
Under the condition of ADT enhancement, increased AR the interaction between the pre -mRNA and splicing factor, increase RNA splicing enhancer and its binding protein (U2AF65 and ASF/SF2) to AR -V7 3 'splice sites raise, lead to the increase of AR -V7 level in prostate cancer cells .
[24]Although the expression of AR -V7 protein relative to AR -FL is low, the low level of AR -V7 are not sufficient to restore the AR activity, but after androgen deprivation induced by fast, [26] the increased ar-v7 was mediated by AR-fl to endue ligand-independent trans-activation of AR, [32] enabling the tumor to retain the basic AR activity needed for survival until a more effective mechanism for AR activation was arise.
[26] AR3 may directly raise AKT1 expression, [23] regulate a variety of tumor autocrine/paracrine factor (Tgf beta 2 and Igf1), raised some epithelium -interstitial conversion related genes such as single or superposition approach to driving of castration resistant prostate cancer. 3.4 ARV1, ARV9, ARV12, ARV13 and ARV14 ARV1 and ARV9 are similar in structure, both of which do not possess the basic amino acids of the two-part nuclear localization sequence, and can be conditionally activated according to the level of androgens. ARV13 and ARV14 had no functional effect, and ARV12 had constitutive activity. The expression levels of ARV12 and ARV9 in CRPC specimens were significantly increased, and ARV12 was positively correlated with patients with Gleason score of 8 or above (P = 0.017). [37]

AR8
AR8 is a new AR splicing variant, mainly located on the plasma membrane, upregulation in castration-resistant prostate cancer cells. AR8 promotes the binding of Src and AR to the EGF receptor in response to EGF treatment and enhances the tyrosine phosphorylation of AR to promote the progression of prostate cancer in the context of androgen deprivation. [38] Conclusion At present, significant breakthroughs have been made in the research on the mechanism and treatment of prostate cancer, especially in the aspects of endocrinology and chemotherapy, which have improved the overall survival time and quality of life for patients. However, when prostate cancer inevitably progresses to the castration resistance stage, the prognosis is still extremely poor. [7]In CRRP, AR-Vs (AR-V7,AR-V567es)was significantly correlated with overall survival, progression-free survival, postoperative biochemical recurrence, and advanced bone metastasis. This paper preliminarily demonstrated the mechanism of AR-Vs in the treatment of abiraterone and enzalutamide resistance in castration-resistant prostate cancer, and also provided directional selection for the treatment of abiraterone, enzalutamide and taxo.
[29] [35]However, the specific mechanism of ar-vs in CRRP still needs to be further studied. It is expected that ar-vs can be used as a therapeutic target to develop effective target inhibitors with little side effects, so as to improve the outcome of poor prognosis of CRRP and improve the overall survival and quality of life of patients. AR-Vs is the key research direction in the future.