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While androgens may function via nuclear androgen receptor (nAR) to increase bladder cancer (BCa) progression, the impact of androgens on muscle invasive BCa, which contains nearly 80% nAR-negative cells, remains unclear. To dissect the androgens potential impacts on these nAR-negative muscle invasive BCa, we first found that the androgens, dihydrotestosterone (DHT) might function via a novel membrane AR (mAR-SLC39A9) to increase nAR-negative BCa cell migration and invasion. Mechanism dissection revealed that DHT/mAR-SLC39A9 might function by altering Gαi protein-mediated MAPK/MMP9 intracellular signaling to increase nAR-negative BCa cell migration and invasion. Preclinical studies using multiple in vitro nAR-negative BCa cell lines and an in vivo mouse model all demonstrated that targeting this newly identified DHT/mAR-SLC39A9/Gαi/MAPK/MMP9 signaling with small molecules mAR-SLC39A9-shRNA or Gαi-shRNA, and not the classic antiandrogens including enzalutamide, bicalutamide, or hydroxyflutamide, could suppress nAR-negative BCa cell invasion. Results from human clinical samples surveys also indicated the positive correlation of this newly identified DHT/mAR signaling with BCa progression and prognosis. Together, these results suggest that androgens may not only function via the classic nAR to increase the nAR-positive BCa cell invasion, they may also function via this newly identified mAR-SLC39A9 to increase the nAR-negative/mAR-positive BCa cell invasion.

A majority of the patients with advanced prostate cancer initially respond to androgen deprivation therapy and enzalutamide therapy, but eventually enter the castration-resistant prostate cancer (CRPC) phase. Some studies have shown that the activation of other signalling pathways in CRPC cells replaces the function of the androgen receptor, as well as promotes cell metastasis and progression. However, the mechanisms underlying this side effect remain unclear. The present study aims to explore the continued progression of cells after enzalutamide resistance. Low expression of circRNA-UCK2 (circUCK2) was detected in enzalutamide-resistant (EnzR) cells. Moreover, miR-767-5p was found to be resistant to EnzR cells when the level of circUCK2 is increased. The decrease in free miR-767-5p increases the expression of TET1 protein through the post-transcriptional regulation of mRNA, thereby inhibiting cell invasion and proliferation. Knocking down circUCK2 in enzalutamide-sensitive cells reduces the concentration of TET1, thereby increasing cell invasion and proliferation. A preclinical study using in vivo mouse models also showed that a high expression of circUCK2 inhibited the EnzR cell growth. Thus, this study might aid in developing a novel therapy to better suppress the CRPC progression.

Prostate cancer (PCa) is one of the most common types of tumors among males worldwide. However, the roles of long noncoding RNAs (lncRNAs) in PCa remain unclear. This study shows that lncRNA FAM83H-AS1 is upregulated in prostate adenocarcinoma, bladder urothelial carcinoma, and kidney renal papillary cell carcinoma samples. Androgen receptor (AR) signaling plays the most important role in PCa tumorigenesis and development. In this study, the results validate that AR signaling is involved in upregulating FAM83H-AS1 expression in PCa cells. Loss-of-function assays demonstrate that FAM83H-AS1 acts as an oncogene in PCa by modulating cell proliferation, cell cycle, and migration. Bioinformatics analysis demonstrates that FAM83H-AS1 is remarkably related to the regulation of the cell cycle and DNA replication through affecting multiple regulators related to these pathways, such as CCNE2. Mechanically, we found that FAM83H-AS1 plays its roles through sponging miR-15a to promote CCNE2 expression. These findings indicate that FAM83H-AS1 is a novel diagnostic and therapeutic marker for PCa.

Background Deaths by COVID-19 have left behind nearly 12 million recent bereaved individuals worldwide and researchers have raised concerns that the circumstances of COVID-19 related deaths will lead to a rise prevalence of prolonged grief disorder (PGD) cases. However, to date, no studies have examined the prevalence of PGD among people bereaved due to COVID-19. This study aimed to estimate the prevalence of PGD and investigated demographic and loss-related factors associated with prolonged grief symptoms among Chinese individuals bereaved due to COVID-19. Methods This was a cross-sectional online survey conducted between September 1 and October 3, 2020. A total of 422 Chinese participants (55.5% males; 32.73 [9.31] years old) who lost a close person due to COVID-19 participated in the study. Demographic and loss-related information was collected, and self-reported prolonged grief symptoms were measured by a 13-item International Prolonged Grief Disorder Scale (IPGDS: 1–65) and a 17-item Traumatic Grief Inventory Self Report (TGI-SR: 1–85). Multiple linear regression analysis was used to determine the associated factors of levels of grief symptoms. Results Prevalence of PGD was 37.8% screened by IPGDS and 29.3% by TGI-SR. No difference was found in levels of grief symptoms between participants whose close one died more than 6 months ago and those who experienced the loss less than 6 months ago. More severe prolonged grief symptoms assessed by IPGDS was associated with losing a close person by COVID-19 rather than complications (B: 5.35; 95% CI: 0.54–10.05), losing a partner (B: 7.80; 95% CI: 3.24–12.37), child (B: 8.15; 95% CI: 1.03–15.26), and parent (B: 5.49; 95% CI: 1.49–9.48) rather than losing a relative or a person with other relationship, feeling more traumatic about the loss (B: 1.71; 95% CI: 0.52–2.90), being closer with the deceased (B: 1.60; 95% CI: 0.34–2.86). Moreover, Losing a grandparent (B: 6.62; 95% CI: 0.53–12.71) and having more conflicts with the deceased (B: 1.05; 95% CI: − 0.008–2.11) were related to higher levels of grief symptoms assessed by TGI-SR. Conclusions Echoing researchers’ concerns, the prevalence of PGD is high among people bereaved due to COVID-19. Individuals with a higher risk of developing PGD should be identified and bereavement support should be offered as early as possible.

MicroRNA-1303 (miR-1303) is involved in the tumorigenesis and progression of several cancers, and yet the role of miR-1303 in prostate cancer (PCa) and its underlying mechanism are unknown. To explore this issue, the present study aimed to use PCa tissues, cell lines and a PCa-engrafted mouse model to determine the expression and roles of miR-1303 in PCa. Furthermore, a series of experiments were conducted to explore the underlying mechanisms of action of miR-1303 in PCa cells. miR-1303 was demonstrated to be highly expressed in PCa tissues and cell lines. The level of miR-1303 expression was closely associated with higher Gleason scores and a more developed tumor stage in patients with PCa, and patients with higher levels of miR-1303 displayed a reduced overall survival rate. miR-1303 overexpression promoted the proliferation, migration and invasion of PCa cells. In vivo experiments showed that miR-1303 inhibition suppressed the growth of PCa tumors in mice. Additionally, dickkopf Wnt signaling pathway inhibitor 3 (DKK3) was identified as a target of miR-1303. Knockdown of miR-1303 suppressed the proliferation, migration and invasion of PCa cells, increased DKK3 expression, and inhibited the activity of the Wnt/β-catenin pathway. In conclusion, miR-1303 may promote proliferation, migration and invasion of PCa cells through activating the Wnt/β-catenin pathway by regulating DKK3 expression. These results indicated that miR-1303 may be considered as a potential biomarker for PCa treatment.

Androgen-deprivation therapy (ADT) with newly developed antiandrogen enzalutamide (Enz) may increase the castration-resistant prostate cancer (CRPC) patients survival an extra 4.8 months. Yet eventually most patients may fail with development of Enz resistance. While recent clinical studies indicated that the increased expression of the androgen receptor (AR) splicing variant ARv7 might have key roles for the development of Enz resistance in CRPC, its detailed mechanism, especially its linkage to the circular RNAs (circRNAs), a form of non-coding RNA, however, remains unclear. Here we found from human clinical sample survey that circRNA17 (hsa_circ_0001427) has a lower expression in higher Gleason score PCa, and results from in vitro cell lines studies also revealed the lower expression in CRPC C4–2 Enz-resistant (EnzR-C4–2) cells compared to their parental Enz-sensitive (EnzS-C4–2) cells. Mechanism dissection indicated that suppressing circRNA17 in EnzS-C4–2 cells increased ARv7 expression that might then lead to increase the Enz resistance and cell invasion. Mechanism dissection demonstrated that Enz could suppress the circRNA17 expression at the transcriptional level via suppressing transcription of its host gene PDLIM5, and circRNA17 could regulate ARv7 expression via altering the expression of miR-181c-5p that involved the direct binding of miR-181c-5p to the 3′UTR of ARv7. Preclinical study using in vivo mouse model with xenografted EnzR-CWR22Rv1 cells revealed that adding circRNA17 or miRNA-181c-5p could suppress the EnzR-CWR22Rv1 cells growth. Together, results from these preclinical studies suggest that circRNA17 may function as suppressor to alter the Enz sensitivity and cell invasion in CRPC cells via altering the miR-181c-5p/ARv7 signaling and targeting this newly identified signaling may help in the development of a better therapy to further suppress the EnzR cell growth.

Background. Attentional bias refers to a preference for (e.g., vigilance) or a shifting away (e.g., avoidance) of one’s focus with respect to specific stimuli. Accumulating evidence suggests that an attentional bias towards death/threat-related stimuli exists in bereaved individuals experiencing prolonged grief (PG). Measuring for different processing may reflect different cognitive characteristics. Therefore, this study sought to compare information-processing biases in Chinese individuals with high versus low levels of PG symptomatology at supraliminal and subliminal levels, respectively. Method. A 2 (grief level) × 2 (consciousness level) × 2 (word type) three-factor mixed design with supraliminal and subliminal tasks was utilized in the current study. Based on their Prolonged Grief Questionnaire-13 (PG-13) scores, 38 participants were included in the low-PG group, and 34 individuals were included in the high-PG group. All the participants completed a dot-probe task in which they were primed with death-related and life-related words paired with neutral stimuli. Results. High-PG individuals were slower in reacting to the death-related information in both supraliminal and subliminal tasks. After controlling for other symptoms in the backwards deletion regression, PG-13 scores significantly predicted the avoidance tendency to death-related words in the supraliminal task, while anxiety was the best predictor of turning one’s vision away from death-related stimuli in the subliminal trials. Conclusions. The results suggested that high PG is associated with a tendency to avoid death-related words. Future research is needed to explore interventions that address the avoidance of death-related stimuli among individuals with elevated, or diagnosable, levels of PG.

// Zuoren Yu 1,2 , Zengguang Xu 1 , Gabriele DiSante 2 , Jennifer Wright 2 , Min Wang 2 , Yuan Li 1 , Qian Zhao 1 , Tao Ren 1 , Xiaoming Ju 2 , Ellen Gutman 2 , Guangxue Wang 1 , Sankar Addya 2 , Tieyan Li 1 , Zhendong Xiang 3 , Chenguang Wang 2 , Xiongfei yang 3 , Xiaolai Yang 3 , Richard Pestell 2 1 Research Center for Translational Medicine, Key Laboratory of Arrhythmias of the Ministry of Education, East Hospital, Tongji University School of Medicine, Shanghai, China, 2 Departments of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia PA 3 People’s Hospital of Gansu Province, Lanzhou, China Correspondence: Richard G. Pestell, email: // Zuoren Yu, email: // Keywords : miR-17/20, breast cancer, AKT, apoptosis Received : January 29, 2014 Accepted : March 2, 2014 Published : March 4, 2014 Abstract The serine threonine kinase Akt1 has been implicated in the control of cellular metabolism, survival and growth. Herein, disruption of the ubiquitously expressed member of the Akt family of genes, Akt1, in the mouse, demonstrates a requirement for Akt1 in miRNA-mediated cellular apoptosis. The miR-17/20 cluster is known to inhibit breast cancer cellular proliferation through G1/S cell cycle arrest via binding to the cyclin D1 3’UTR. Here we show that miR-17/20 overexpression sensitizes cells to apoptosis induced by either Doxorubicin or UV irradiation in MCF-7 cells via Akt1. miR-17/20 mediates apoptosis via increased p53 expression which promotes Akt degradation. Akt1 -/- mammary epithelial cells which express Akt2 and Akt3 demonstrated increased apoptosis to DNA damaging agents. Akt1 deficiency abolished the miR-17/20-mediated apoptosis. These results demonstrated a novel pathway through which miR17/20 regulate p53 and Akt controlling breast cancer cell apoptosis.

Prostate cancer (PCa) is one of the leading causes of cancer-related death worldwide, and it is almost incurable once it has developed into castration-resistance prostate cancer (CRPC). However, the mechanisms underlying the oncogenesis of PCa and CRPC remain elusive. Lysine-specific histone demethylase 5C (KDM5C) is an important member of lysine demethylase family and has recently been found highly expressed in multiple cancer types. In this study, we reported that KDM5C was highly expressed in PCa and CRPC specimens, and the high expression promoted CRPC cell proliferation through repressing phosphatase and tensin homolog (PTEN) gene epigenetically. Moreover, KDM5C was transcriptionally upregulated by bromodomain-containing protein 4 (BRD4), and knockdown KDM5C sensitized the therapeutic effects of CRPC cells to the bromodomain and extraterminal (BET) inhibitor. Taken together, our study uncovers that the BRD4-KDM5C-PTEN may be a new oncogenic pathway in CRPC development, and KDM5C is a critical protein and could be an ideal target for CRPC treatment in this oncogenic pathway.