Thymoquinone is an anticancer phytochemical commonly found in black cumin. In this review, we discuss the potential of thymoquinone as anticancer molecule, its mechanism of action and future usage in clinical applications. Thymoquinone exhibits anticancer activity via numerous mechanisms of action, specifically by showing selective antioxidant and oxidant activity, interfering with DNA structure, affecting carcinogenic signaling molecules/pathways and immunomodulation. In vitro activity of thymoquinone has been further implicated in animal models of cancer; however, no clinical application has been proven yet. This is the optimum time to focus on clinical trials for developing thymoquinone as a future drug in cancer therapeutics.

MicroRNA-34a (miR-34a) plays an essential role against tumorigenesis and progression of cancer metastasis. Here, we analyzed the expression, targets and functional effects of miR-34a on epithelial to mesenchymal transition-inducing transcription factors (EMT-TFs), such as TWIST1, SLUG and ZEB1/2, and an EMT-inducing protein NOTCH1 in breast cancer (BC) cell migration and invasion and its correlation with tumorigenesis and clinical outcomes. Expression of miR-34a is downregulated in human metastatic breast cancers (MBC) compared to normal breast tissues and is negatively correlated with clinicopathological features of MBC patients. Ectopic expression of miR-34a in MBC cell-line BT-549 significantly inhibits cell migration and invasion, but exhibits no clear effect on BC cell growth. We found that miR-34a is able to inactivate EMT signaling pathway with mediatory of NOTCH1, TWIST1, and ZEB1 upon 3′-UTR activity in MBC cell lines, but has no inhibitory effects on SLUG and ZEB2. Furthermore, we investigated the synergistic effects of Thymoquinone (TQ) and miR-34a together on the expression of EMT-associated proteins. Results showed that co-delivery of miR-34a and TQ is able to inactivate EMT signaling pathway by directly targeting TWIST1 and ZEB1 in BT-549 cell line, indicating that they might be a promising therapeutic combination against breast cancer metastasis. Epigenetic inactivation of the EMT-TFs/miR-34a pathway can potentially alter the equilibrium of these regulations, facilitating EMT and metastasis in BC. Altogether, our findings suggest that miR-34a alone could serve as a potential therapeutic agent for MBC, and together with TQ, their therapeutic potential is synergistically enhanced.

BackgroundMicroRNA-34a (miR-34a) is a master regulator of tumor suppression in breast cancer (BC). This systematic review aims to analyze the diagnostic accuracy of miR-34a in the detection of BC as a biomarker.ResultsA total of 1858 BC cases and 494 controls from thirteen eligible studies reported in 9 publications were included. The overall pooled sensitivity, specificity, negative likelihood ratio (NLR), positive likelihood ratio (PLR), and diagnostic odds ratio (DOR) were 85.50% (95% CI: 83.80-87.00%), 70.00% (95% CI: 65.80–74.10%), 0.29 (95% CI: 0.19–0.43), 2.58 (95% CI: 1.91–3.43), and 9.39 (95% CI: 5.47–16.12), respectively. Similarly, the overall area under the curve (AUC) of the summary receiver operating characteristic (SROC) was 0.80, indicating the high conservation of miR-34a as a biomarker. Furthermore, subgroup analysis suggested that the use of miR-34a as a biomarker is more accurate in tissue-based sample of invasive BC. We also indicated that miR-34a is a capable biomarker in diagnosing BC in people of Caucasian descent.Materials and MethodsA systematic search was conducted for eligible publications that address miR-34a expression level in BC cases and noncancerous controls. Diagnostic capacity of miR-34a for BC was assessed using pooled sensitivity and specificity, DOR, and AUC of SROC. PLR and NLR were verified to estimate the miR-34a diagnostic accuracy in clinical level. The quality of the included studies was assessed by QUADAS-2.ConclusionsThese findings suggest miR-34a is a promising non-invasive biomarker in diagnosing BC. Well-designed cohort studies should be implemented to warrant the diagnostic value of miR-34a in clinical purposes.

Leber congenital amaurosis (LCA) is a heterogeneous, early‐onset inherited retinal dystrophy, which is associated with severe visual impairment. We aimed to determine the disease‐causing variants in Iranian LCA and evaluate the clinical implications. Clinically, a possible LCA disease was found through diagnostic imaging, such as fundus photography, autofluorescence and optical coherence tomography. All affected patients showed typical eye symptoms associated with LCA including narrow arterioles, blindness, pigmentary changes and nystagmus. Target exome sequencing was performed to analyse the proband DNA. A homozygous novel c. 2889delT  (p.P963 fs) mutation in the RPGRIP1 gene was identified, which was likely the deleterious and pathogenic mutation in the proband. Structurally, this mutation lost a retinitis pigmentosa GTPase regulator (RPGR)‐interacting domain at the C‐terminus which most likely impaired stability in the RPGRIP1 with the distribution of polarised proteins in the cilium connecting process. Sanger sequencing showed complete co‐segregation  in this pedigree. This study provides compelling evidence that the c. 2889delT  (p.P963 fs) mutation in the RPGRIP1 gene works as a pathogenic mutation that contributes to the progression of LCA.