Current Molecular Medicine (v.16, #8)

Meet Our Associate Editor by Michelangelo Mancuso (689-689).

Reprogramming of Molecular Switching Events in UPR Driven ER Stress: Scope for Development of Anticancer Therapeutics by B. Rah, D. Nayak, R. Rasool, S. Chakraborty, A. Katoch, H. Amin, A. Goswami (690-701).
The incitement of unfolded protein response (UPR) during endoplasmic reticulum (ER) stress by diverse intracellular (hypoxia, nutrient deprivation, etc.) or extracellular (environmental or drug induced) stimuli is considered a major threat for perturbing cellular homeostasis leading to the aggregation of unfolded proteins inside the cell. The catastrophic UPR events emerge as a prime cellular adaptation by remodeling cancer cell signaling and restoring ER homeostasis in favor of tumor growth. The transient ER stress protects cancer cells from undergoing apoptosis, whereas the prolonged stress response further activates many cell death pathways. The present review summarizes the UPR mediated triggering of transcriptional and translational reprogramming, which will provide novel therapeutic strategies towards pro-death mechanisms rather than a cellular adaptation in tumorigenesis. Nonetheless, the current topic also points out the reprogramming of emerging molecular switching events by complex UPR-mediated signaling to trigger apoptosis. The novel agents from various natural, semi-synthetic and synthetic sources that target ER stress signaling pathway to modulate selectively the UPR phenomena with preclinical efficacy are outlined. Since major emphasis on ER stress-induced transcriptional and translational reprogramming remains to be explored, we believe that the current subject will instigate more attention from the biomedical researchers in this certain research direction.

Long Non-Coding RNA: An Emerging Paradigm of Pancreatic Cancer by T. Han, H. Hu, M. Zhuo, L. Wang, J.-J. Cui, F. Jiao, L.-W. Wang (702-709).
Pancreatic cancer remains a worldwide issue and burden that is hard to resolve given its low resection rate and chemo-resistance. Early diagnosis and early treatment are critical for conquering pancreatic cancer. Therefore, new biomarkers for diagnosis and prognosis are urgently needed. Previously, researchers mainly focused on protein-coding genetic and epigenetic changes in many types of cancers, and regarded the noncoding part as waste. Recently, however, long non-coding RNA (lncRNA) has emerged as a major participant in carcinogenesis, as it regulates cell proliferation, migration, invasion, metastasis, chemo-resistance, etc. The underlying mechanisms are summarized as signaling, decoy, guide and scaffold, yet the specific regulation networks remain to be uncovered. Several studies have revealed that some lncRNAs are dysregulated in pancreatic cancer, participating in biological functions. In this review, we will briefly outline the functional lncRNAs in pancreatic cancer, decipher possible mechanisms of lncRNAs, and further explore their significance in pancreatic cancer.

Novel Aspects in the Pathogenesis of Nonalcoholic Steatohepatitis by A. Gentilini, A. Caligiuri, A. Provenzano, F. Marra (710-720).
Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease, characterized by inflammation, hepatocyte injury and fibrogenesis. Overall mortality, and liver-related mortality, are both increased in NASH patients. Considering that nonalcoholic fatty liver disease is the most prevalent hepatic abnormality in the Western world, understanding the mechanisms leading to NASH and its progression to cirrhosis is critical for a better management of these patients. Moreover, a more detailed knowledge of this condition may be helpful to identify those subjects which are more susceptible to develop progressive liver disease. Emerging data indicate that NASH progression results from parallel events originating from the liver as well as from the adipose tissue, and the gastrointestinal tract. In this review we highlight some of the most recent findings reported on the pathogenesis of NASH and its fibrogenic progression to cirrhosis, in an effort to identify possible targets for treatment or biomarkers of disease progression.

NAFLD (Non-Alcoholic Fatty Liver Disease) is an increasingly significant public health issue, regarded as the most relevant liver disease of the twenty-first century. Approximately 20%-30% of NAFLD subjects develop a NASH (Non-Alcoholic Steato-Hepatitis), a condition which can potentially evolve to liver cirrhosis and hepatocellular carcinoma. For these reasons a proper evaluation of liver damage is a key point for diagnosis and prognosis and liver biopsy still remains the “gold standard” procedure both for discrimination between steatosis and steatohepatitis and assessment of the degree of liver fibrosis. Nonetheless, given it is an invasive, painful and costly procedure, a great research efforts have been made in order to develop non-invasive methods for the assessment of NAFLD presence and/or severity by serum markers and imaging techniques. In this review we aimed to perform a comprehensive review of the literature about strengths and weaknesses of the main tools available for the non-invasive assessment of NAFLD patients.

Background: Cell cycle regulation of neural progenitor cells (NPCs) is an essential process for neurogenesis, neural development, and repair after brain trauma. Stromal cell-derived factor-1 (SDF-1, CXCL12) and its receptors CXCR4 and CXCR7 are well known in regulating the migration and survival of NPCs. The effects of CXCL12 on NPCs proliferation, cell cycle regulation, and their associated signaling pathways remain unclear. Cyclin D1 is a protein required for progression through the G1 phase of the cell cycle and a known downstream target of ? -catenin. Therefore, cyclin D1 plays critical roles of cell cycle regulation, proliferation, and survival in NPCs.
Methods: Primary mouse NPCs (mNPCs) were derived from brain tissues of wild-type, Cxcr4 knockout, or Cxcr7 knockout mice at mouse embryonic day 13.5 (E13.5). Flow cytometry was used to perform cell cycle analysis by quantitation of DNA content. Real-time PCR and Western blot were used to evaluate mRNA and protein expressions, respectively. Ki67 immunostaining and TUNEL assay were used to assess the proliferation and survival of mNPCs, respectively.
Results: CXCL12 pretreatment led to the shortening of G0/G1 phase and lengthening of S phase, suggesting that CXCL12 regulates cell cycle progression in mNPCs. Consistently, CXCL12 treatment increased the expression of CyclinD1 and ? -catenin, and promoted proliferation and survival of mNPCs. Cxcr7 knockout of mNPCs blocked CXCL12-mediated mNPCs proliferation, whereas Cxcr4 knockout mNPC did not significantly effect CXCL12- mediated mNPCs proliferation.
Conclusion: CXCR7 plays an important role in CXCL12-mediated mNPC cell cycle regulation and proliferation.

Objectives: The present study was designed to investigate the effects of calcitriol (the active hormonal metabolite of vitamin D) on hepatic metabolic abnormalities in type 2 diabetes.
Methods: Type 2 diabetic db/db mice were used to investigate the effects of calcitriol on hepatic and systemic metabolic disorders. HepG2 cells cultured in insulin-resistant conditions were used to examine the potential mechanisms for calcitriol-induced changes in hepatic lipid and glucose metabolism.
Results: 8-week calcitriol treatment ameliorated abnormal hepatic lipid and glucose production in db/db mice. In HepG2 cells under insulin-resistant condition, calcitriol increased cytosolic calcium concentration and induced 5'-AMP-activated protein kinase/acetyl-CoAcarboxylase (AMPK/ACC) phosphorylation via the Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ) pathway, contributing to the reductions in hepatic triglyceride accumulation and glucose output. Calcitriol also induced AMPK/ACC phosphorylation in liver of db/db mice.
Conclusion: Our data indicate that calcitriol, at above-physiological serum concentrations, reduces hepatic triglyceride accumulation and glucose output, at least in part through activation of Ca2+/CaMKKβ/AMPK under insulin-resistant condition.

Clinical Experience of Non-Invasive Prenatal Chromosomal Aneuploidy Testing in 190,277 Patient Samples by H. Hu, H. Liu, C. Peng, T. Deng, X. Fu, C. Chung, E. Zhang, C. Lu, K. Zhang, Z. Liang, Y. Yang (759-766).
Objectives: To detect trisomy 21, 18, and 13 in 190,277 clinical samples from the medical diagnostic laboratories of ten hospitals.
Methods: The study assessed the clinical performance of non-invasive prenatal testing (NIPT) in detecting trisomy 21, 18, and 13 in 190,277 clinical samples using semiconductor sequencing technology.
Results: NIPT participants were at a mean gestation of 17.79 weeks (range, 9-36) and age of 31.12 years (range, 18-46) at the time of testing on average. There were 1,543 (0.81%) positive cases, including 1050 for trisomy 21, 316 for trisomy 18, and 177 for trisomy, 13. The overall sensitivity and specificity for detecting trisomy 21, 18 and 13 combined were 99.61% and 99.91% respectively, and the overall positive predictive value and negative predictive value (PPV and NPV) were 89.74% and 99.99%, respectively.
Conclusions: This was the first large clinical study for semiconductor sequencing technologies in NIPT application. Our findings indicate that NIPT has the potential to replace serum biochemistry screening and could be performed at the early gestational age of 9~12 weeks.

STIP Regulates ERK1/2 Signaling Pathway Involved in Interaction with PP1? in Lymphoblastic Leukemia by S. Sun, Y. Wang, H. Chen, L. Fang, Y. Cui, X. Han, D. Wu, H. Li, M. Ye, X. Zhao, J. Liu (767-775).
Background: Sip1/Tuftelin Interacting Protein (STIP) is highly conserved from Caenorhabditis elegans to Homo sapiens and has essential biological functions. However, its function in leukemia remains unknown.
Methods: Clinic samples and cell model were used in this article to investigate the expression of STIP in lymphoblastic leukemia. The functional research of STIP was performed in ARH-77 by siRNA transfection, immunofluorescence, cell count, cell cycle analysis, qRT-PCR, sub-cellular fractionation assays, immunoprecipitation and western blotting.
Results: Here, we found that STIP is more highly expressed in both clinical lymphoblastic leukemia samples and cultured leukemia cells than in normal samples. Knockdown of STIP in B lymphoblastic leukemia ARH-77 cells leads to S phase arrest, lower cell proliferation rates, and suppressed AKT and ERK1/2 signaling pathways. Interestingly, when protein phosphatase was inhibited by Calyculin A, STIP knockdown did not result in the dephosphorylation of p-ERK1/2, suggesting the dependence of STIP on protein phosphatase in the regulation of ERK1/2. Among those protein phosphatase inhibited by Calyculin A, PP1? was found to interact with STIP proven by immunofluorescence and immunoprecipitation assays. The binding of STIP with PP1? may decrease the phosphatase activity of PP1?, resulting in hyper-activated ERK1/2 signaling.
Conclusion: In summary, the high expression and activation effect on the ERK1/2 signaling of STIP in lymphoblastic leukemia suggest that STIP would be a potential therapy target or diagnosis marker for leukemia.