Kale Ajay, Aldahish Afaf, Shah Girish
Pharmacology, University of Louisiana College of Pharmacy, Monroe, LA 71201, USA.
Oncotarget. 2020 Mar 3;11(9):858-874. doi: 10.18632/oncotarget.27495.
Expression of calcitonin (CT) and its receptor (CTR) is frequently elevated in prostate cancer (PC) and activation of CT-CTR axis in non- invasive PC cells induces an invasive phenotype. However, the role of CT-CTR axis in prostate carcinogenesis has not been investigated. We employed a transgenic mouse prostate cancer model that uses long probasin promoter to target the expression of T-antigen in the prostate gland (LPB-Tag) along with CTR knock-out mice (CTRKO) to address this question. We cross-bred LPB-Tag mice with CTRKO to obtain four groups of mice. Prostates of these mice were obtained at the age of 90 days, fixed, paraffin-embedded, and used either for the extraction of RNA or for immunofluorescence. Prostate RNAs from different groups were reverse transcribed and used either for transcription profiling or for qRT-PCR. As expected, prostates of mice with LPB-Tag genotype displayed well-grown tumors with histologic features such as loss of normal morphology and nuclear atypia. WT as well as CTRKO mice displayed normal prostate morphology. Interestingly, LPB-Tag-CTRKO prostates also displayed relatively normal morphology which was indistinguishable from the WT. Microarray analysis as well as qRT-PCR suggested that CTRKO genotype reversed T-antigen-induced silencing of RB and PTEN gene expression as well as T-antigen-induced expression of several enzymes associated with lipid metabolism/ cholesterol biosynthesis, several cancer-related and androgen-regulated genes. The results for the first time identify mechanisms associated CTR-induced prostate carcinogenesis, and raise an exciting possibility of using a potent CT antagonist to attenuate progression of prostate cancer.
降钙素（CT）及其受体（CTR）的表达在前列腺癌（PC）中常常升高，并且在非侵袭性PC细胞中CT-CTR轴的激活会诱导侵袭性表型。然而，CT-CTR轴在前列腺癌发生中的作用尚未得到研究。我们采用了一种转基因小鼠前列腺癌模型，该模型使用长型前列腺素启动子来靶向T抗原在前列腺中的表达（LPB-Tag），并结合CTR基因敲除小鼠（CTRKO）来解决这个问题。我们将LPB-Tag小鼠与CTRKO小鼠杂交，获得四组小鼠。在90日龄时获取这些小鼠的前列腺，固定、石蜡包埋，然后用于RNA提取或免疫荧光分析。来自不同组的前列腺RNA进行逆转录，用于转录谱分析或qRT-PCR。正如预期的那样，具有LPB-Tag基因型的小鼠前列腺呈现出生长良好的肿瘤，具有组织学特征，如正常形态丧失和核异型性。野生型（WT）以及CTRKO小鼠的前列腺形态正常。有趣的是，LPB-Tag-CTRKO前列腺也呈现出相对正常的形态，与WT难以区分。微阵列分析以及qRT-PCR表明，CTRKO基因型逆转了T抗原诱导的RB和PTEN基因表达沉默，以及T抗原诱导的几种与脂质代谢/胆固醇生物合成相关的酶、几种癌症相关和雄激素调节基因的表达。这些结果首次确定了与CTR诱导的前列腺癌发生相关的机制，并提出了使用强效CT拮抗剂来减缓前列腺癌进展的令人兴奋的可能性。
