Breast cancer stem cells (BCSCs) are believed to be responsible for tumor chemoresistance, recurrence, and metastasis formation. Salinomycin (SAL), a carboxylic polyether ionophore, has been reported to act as a selective breast CSC inhibitor. However, the molecular mechanisms underlying SAL-induced cytotoxicity on BCSCs remain unclear. The Hedgehog (Hh) signaling pathway plays an important role in CSC maintenance and carcinogenesis. Here, we investigated whether SAL induces cytotoxicity on BCSCs through targeting Hh pathway. In the present study, we cultured breast cancer MCF-7 cells in suspension in serum-free medium to obtain breast CSC-enriched MCF-7 mammospheres (MCF-7 MS). MCF-7 MS cells possessed typical BCSC properties, such as CD44+CD24-/low phenotype, high expression of OCT4 (a stem cell marker), increased colony-forming ability, strong migration and invasion capabilities, differentiation potential, and strong tumorigenicity in xenografted mice. SAL exhibited selective cytotoxicity to MCF-7 MS cells relative to MCF-7 cells. The Hh pathway was highly activated in BCSC-enriched MCF-7 MS cells and SAL inhibited Hh signaling activation by downregulating the expression of critical components of the Hh pathway such as PTCH, SMO, Gli1, and Gli2, and subsequently repressing the expression of their essential downstream targets including C-myc, Bcl-2, and Snail (but not cyclin D1). Conversely, Shh-induced Hh signaling activation could largely reverse SAL-mediated inhibitory effects. These findings suggest that SAL-induced selective cytotoxicity against MCF-7 MS cells is associated with the inhibition of Hh signaling activation and the expression of downstream targets and the Hh pathway is an important player and a possible drug target in the pathogenesis of BCSCs.

This study aimed to evaluate the effects of thyroid-stimulating hormone (TSH) suppressive therapy on bone mineral density (BMD) and bone turnover markers (BTMs) in differentiated thyroid cancer (DTC) patients after postoperative 1-2 years in Northeast China. MethodsFive male, sixteen premenopausal, and eight postmenopausal female DTC patients receiving TSH suppressive therapy after thyroidectomy were enrolled. Patients were matched with healthy controls in a ratio of 1:2. All participants completed postoperative 1-year follow-up, and postmenopausal women completed 2-year follow-up. We measured BMD of the lumbar spine (LS), femoral neck (FN), and total hip (TH) using dualenergy X-ray absorptiometry (DXA). Bone formation marker P1NP and bone resorption marker β-CTX were also evaluated. Fracture risks were assessed by FRAX. ResultsThere was no difference in BMD and BTMs between DTC patients and controls in the male group at 1-year follow-up. In the premenopausal women, the LS-BMD, FN-BMD, and TH-BMD in DTC patients were all higher than those in controls, but only FN-BMD showed a signi cant difference. The change rate of P1NP showed a signi cant difference between DTC patients and controls, while no difference was found in the β-CTX level. In the postmenopausal women, no difference in BMD and BTMs were observed between DTC patients and controls at the 1-year and 2-year follow-up. ConclusionOur study indicated that postoperative 1-year TSH suppressive therapy did not show detrimental effects on BMD and BTMs in men, premenopausal, and postmenopausal DTC patients. The 2-year postoperative TSH suppressive therapy did not lead to additional loss of bone mass in postmenopausal DTC patients.Up to date, few prospective longitudinal studies [5-9] have been reported and the studies in mainland China are limited [10,11]. To the best of our knowledge, no prospective cohort study has been conducted in China. This prospective controlled cohort study aimed to evaluate BMD and BTMs in male, premenopausal female and postmenopausal female DTC patients receiving TSH suppressive therapy at postoperative 1 year in northeast China. Postoperative 2-year follow-up was conducted in postmenopausal female DTC patients. Materials And Methods Patients and selection criteriaThe study population consisted of patients who underwent operation for DTC from 2012 to 2014 at the First A liated Hospital of China Medical University. The following inclusion criteria were used: (1) patients who were diagnosed with DTC underwent total or subtotal thyroidectomy; (2) BMD was tested and serum sample was obtained before operation; (3) TSH suppressive therapy using LT4 was conducted immediately after thyroidectomy, the goal of TSH suppressive level was less than 0.5 mIU/L. The exclusion criteria included: (1) recurrence and distant metastasis; (2) parathyroid injury presented with abnormal serum calcium, phosphate, and parathyroid hormone due to thyroidectomy; (3) showing symptoms of thyrotoxicosis and forced to stop TSH suppressive therapy; (4) use of drugs affe...

Rationale: Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related deaths and the sixth most commonly diagnosed cancer globally. Interdisciplinary and multimodal treatment strategies are essential for a successful therapy in HCC. Established therapies for HCC treatment include surgical resection, liver transplantation, local ablative therapies, transarterial chemoembolization (TACE), tyrosine kinase inhibitors (TKIs), immunotherapy, and radiotherapy (RT). Patient concerns: A 52-year-old male patient did an ultrasound scan and found a large mass within the right lobe of the liver and gallstones in December 2018. He had a history of chronic hepatitis C virus infection (30 years) and was treated with sofosbuvir (400 mg, q.d.) for 1 year. The patient never had any symptoms of gallstones. Enhanced abdominal computed tomography of this patient showed a heterogeneous irregular mass with the largest measurement of up to 13.7 × 11.1 cm in size in the right lobe of the liver, meanwhile also had inferior vena cava (IVC) tumor thrombus, right atrial (RA) tumor thrombus, and left adrenal gland metastasis. The laboratory test data revealed that the serum tumor marker α-fetoprotein was 2.63 ng/mL, cancer antigen 19-9 (CA 19-9) was 34.40 U/mL, and protein induced by Vitamin K absence was 391.94 mAU/mL. Diagnosis: HCC with IVC tumor thrombus, RA tumor thrombus, and left adrenal gland metastasis, and gallstones. Interventions: He was hospitalized and received TACE treatment, oral TKIs, intravenous drip programmed cell death-1 (PD-1) inhibitor and RT. Outcomes: The patient showed a favorable response after consecutive treatment with TACE, TKIs, PD-1 inhibitor, and RT. Until now, the patient has survived 34 months since the diagnosis of the disease. Lessons: Our case suggests that TACE combined with TKIs, PD-1 inhibitor, and RT may be a suitable treatment option for advanced HCC patients with IVC tumor thrombus and/or RA tumor thrombus, and/or adrenal gland metastasis.

Nemo-like kinase (NLK), an evolutionarily conserved serine/threonine kinase, has been recognized as a critical regulator of various cancers. In this study, we investigated the role of NLK in human small-cell lung cancer (SCLC), which is the most aggressive form of lung cancer. NLK expression was evaluated by quantitative real-time polymerase chain reaction in 20 paired fresh SCLC tissue samples and found to be noticeably elevated in tumor tissues. Lentivirus-mediated RNAi efficiently suppressed NLK expression in NCI-H446 cells, resulting in a significant reduction in cell viability and proliferation in vitro. Moreover, knockdown of NLK led to cell cycle arrest at the S-phase via suppression of Cyclin A, CDK2, and CDC25A, which could contribute to cell growth inhibition. Furthermore, knockdown of NLK decreased the migration of NCI-H446 cells and downregulated matrix metalloproteinase 9. Treatment with NLK short hairpin RNA significantly reduced SCLC tumor growth in vivo. In conclusion, this study suggests that NLK plays an important role in the growth and metastasis of SCLC and may serve as a potential therapeutic target for the treatment of SCLC.