Identification of specific genes and pathways involved in NSAIDs-induced apoptosis of human colon cancer cells

AIM: To study whether indomethacin (IND), a nonselective cyclooxygenase (COX) inhibitor or NS-398 (NS), a COX-2-selective inhibitor, induces apoptosis in human colon cancer cells and which apoptosis-related genes and pathways are involved. METHODS: Human colon cancer Caco-2 cells were treated with either: placebo, IND (0.05-0.5 mmol/L) or NS (0.01-0.2 mmol/L) for 1, 5 and 18 h. We then studied: (1) Cell death by the TUNEL method, (2) mRNA expression of 96 apoptosis-related genes using DNA microarray, (3) expression of selected apoptosis related proteins by Western blotting. RESULTS: Both IND and NS induced apoptosis in 30%-50% of Caco-2 cells in a dose dependent manner. IND (0.1 mmol/L for 1 h) significantly up-regulated pro-apoptotic genes in four families: (1) TNF receptor and ligand, (2) Caspase, (3) Bcl-2 and (4) Caspase recruiting domain. NS treatment up-regulated similar pro-apoptotic genes as IND. In addition, IND also down-regulated anti-apoptotic genes of the IAP family. CONCLUSION: (1) Both non-selective and COX-2-selective NSAIDs induce apoptosis in colon cancer cells in a dose dependent manner. (2) Both NSAIDs induce apoptosis by activating two main apoptotic pathways: the death receptor pathway (involving TNF-R) and the mitochondrial pathway. (3) IND induces apoptosis by up-regulating pro-apoptotic genes and down-regulating anti-apoptotic genes, while NS only up-regulates pro-apoptotic genes. (4) Induction of apoptosis in coloncancer cells by NSAIDs may explain in part, their inhibitory action on colon cancer growth.

Serum response factor:Look into the gut

Serum response factor(SRF) is a transcription factor that regulates many genes involved in cellular activities such as proliferation,migration,differentiation,angiogenesis,and apoptosis.Although it has only been known for about two decades,SRF has been studied extensively.To date,over a thousand SRF studies have been published,but it still remains a hot topic.Due to its critical role in mesoderm-derived tissues,most of the SRF studies focused on muscle structure/function,cardiovascular development/maintenance,and smooth muscle generation/repair.Recently,SRF has received more attention in the digestive field and several important discoveries have been made.This review will summarize what we have learned about SRF in the gastrointestinal tract and provide insights into possible future directions in this area.

Potential of casein kinase I in digestive cancer screening

Casein kinase I is a group of ubiquitous Serine/Threonine kinases that have been implicated in both normal cellular functions and several pathological conditions including Alzheimer's disease and cancer.Recent findings in colon and pancreatic cancer have brought tremendous attention to these molecules as potential therapeutic targets in treatment of digestive cancers.In this review,we summarize up to date what is known about this family of kinases and their involvement in carcinogenesis and other pathological conditions.Our emphasis is on their implications in digestive cancers and their potential for cancer screening and therapy.

Psychiatric and substance use disorders co-morbidities and hepatitis C: Diagnostic and treatment implications

Chronic hepatitis C virus(HCV) viral infection is the most common blood-borne viral infection and approximately 2%-3% of the world's population or 170-200 million people are infected. In the United States as many as 3-5 million people may have HCV. Psychiatric and substance use disorders(SUDs) are common co-morbid conditions found in people with HCV and are factors in predisposing people to HCV infection. Also, these co-morbidities are reasons that clinicians exclude people from antiviral therapy in spite of evidence that people with HCV and co-morbid psychiatric and SUD can be safely and effectively treated. Furthermore, the neuropsychiatric side effects of interferon(IFN), until recently the mainstay of antiviral therapy, have necessitated an appreciation and assessment of psychiatric co-morbidities present in people with HCV. The availability of new medications and IFNfree antiviral therapy medication combinations will shorten the duration of treatment and exposure to IFN and thus decrease the risk of neuropsychiatric side effects. This will have the consequence of dramatically altering the clinical landscape of HCV care and will increase the number of eligible treatment candidates as treatment of people with HCV and co-morbid psychiatric and SUDs will become increasingly viable. While economically developed countries will rely on expensive IFN-free antiviral therapy, less developed countries will likely continue to use IFN-based therapies at least until such time as IFNfree antiviral medications become generic. The current manuscript discusses the efficacy and viability of treating HCV in people with psychiatric and SUDs comorbidities, the treatment of the neuropsychiatric side effects of IFN-based therapies and the impact of new medications and new treatment options for HCV that offer the promise of increasing the availability of antiviral therapy in this vulnerable population.

S100A4 in esophageal cancer:Is this the one to blame?

Metastasis is the main reason for cancer-related death.S100A4 is one of the key molecules involved in this event.Several studies have shown that overexpression of S100A4 in non-metastatic cancer cells can make them become metastatic,and knockdown of S100A4 in metastatic cancer cells can curtail their invasive nature.A study by Chen et al published in the World J Gastroenterol 18(9):915-922,2012 is a typical example.This study showed in vitro and in vivo evidence that S100A4 expression level determines the invasiveness of esophageal squamous carcinoma.Considering the fact that more than half of the cancer-related deaths are caused by malignancies derived from the digestive system and esophageal cancer is the 4th top contributor to this fraction,this study warrants more attention.

Changes in tumor-antigen expression profile as human small-cell lung cancers progress

Objective： Our group has previously observed that in patients with small-cell lung cancers （SCLCs）, the expression of a tumor antigen, glioma big potassium （gBK） ion channel, is higher at the time of death than when the cancer is first treated by surgical resection. This study aimed to determine whether this dichotomy was common in other potential lung tumor antigens by examining the same patient samples using our more extensive profile analysis of tumor-antigen precursor protein （TAPP）. We then tested the hypothesis that therapeutic intervention may inadvertently cause this increased gBK production. Methods： SCLC samples （eight surgical resections and three autopsy samples） and three control lungs were examined by quantitative real-time polymerase chain reaction for 42 potential TAPPs that represent potential T-cell-mediated immunological targets. Results： Twenty-two TAPP mRNAs displayed the same profile as gBK, i.e., more mRNAs were expressed at autopsy than in their surgical counterparts. B-cyclin and mouse double minute 2, human homolog of PS3-binding protein were elevated in both autopsy and surgical specimens above the normal-lung controls. When HTB119 cells were incubated with doxorubicin, gBK was strongly induced, as confirmed by intracellular flow cytometry with a gBK-specific antibody. Conclusion： Our findings suggested that more immunological targets became available as the tumor responded to chemotherapy and proceeded toward its terminal stages.

Esophageal malignancy:A growing concern

Esophageal cancer is mainly found in Asia and east Africa and is one of the deadliest cancers in the world.However,it has not garnered much attention in the Western world due to its low incidence rate.An increasing amount of data indicate that esophageal cancer,particularly esophageal adenocarcinoma,has been rising by 6-fold annually and is now becoming the fastest growing cancer in the United States.This rise has been associated with the increase of the obese population,as abdominal fat puts extra pressure on the stomach and causes gastroesophageal reflux disease(GERD).Long standing GERD can induce esophagitis and metaplasia and,ultimately,leads to adenocarcinoma.Acid suppression has been the main strategy to treat GERD;however,it has not been proven to control esophageal malignancy effectively.In fact,its side effects have triggered multiple warnings from regulatory agencies.The high mortality and fast growth of esophageal cancer demand more vigorous efforts to look into its deeper mechanisms and come up with better therapeutic options.

The peripheral T-cell lymphoma:can we pivot from the chemotherapy-predicated paradigm?

Peripheral T-cell lymphomas(PTCL)are uncommon and aggressive diseases that are difficult to study.Combination chemotherapy such as cyclophosphamide,doxorubicin,vincristine,and prednisone has been the mainstay of treatment for almost 30 years,but outcomes remain poor.The development of new targeted therapies is changing the landscape of how we treat patients with these difficult diseases.For instance,the addition of brentuximab vedotin to combination chemotherapy enhanced the outcomes in patients with CD30-positive anaplastic large cell lymphomas,but there is still a need for better therapies in the other numerous subtypes.Here we discuss the data for the existing treatment paradigm of PTCL as well as the merits of shifting toward a chemotherapy-free approach.