Apoptosis is the programmed cell death which maintains the healthy survival/death balance in metazoan cells. Defect in apoptosis can cause cancer or autoimmunity, while enhanced apoptosis may cause degenerative diseases. The apoptotic signals contribute into safeguarding the genomic integrity while defective apoptosis may promote carcinogenesis. The apoptotic signals are complicated and they are regulated at several levels. The signals of carcinogenesis modulate the central control points of the apoptotic pathways, including inhibitor of apoptosis (IAP) proteins and FLICE-inhibitory protein (c-FLIP). The tumor cells may use some of several molecular mechanisms to suppress apoptosis and acquire resistance to apoptotic agents, for example, by the expression of antiapoptotic proteins such as Bcl-2 or by the downregulation or mutation of proapoptotic proteins such as BAX. In this review, we provide the main regulatory molecules that govern the main basic mechanisms, extrinsic and intrinsic, of apoptosis in normal cells. We discuss how carcinogenesis could be developed via defective apoptotic pathways or their convergence. We listed some molecules which could be targeted to stimulate apoptosis in different cancers. Together, we briefly discuss the development of some promising cancer treatment strategies which target apoptotic inhibitors including Bcl-2 family proteins, IAPs, and c-FLIP for apoptosis induction.

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The tumor suppressor gene p53 has been implicated in the regulation of epithelial–mesenchymal transition (EMT) and tumor metastasis by regulating microRNA (miRNA) expression. Here, we report that mutant p53 exerts oncogenic functions and promotes EMT in endometrial cancer (EC) by directly binding to the promoter of miR-130b (a negative regulator of ZEB1) and inhibiting its transcription. We transduced p53 mutants into p53-null EC cells, profiled the miRNA expression by miRNA microarray and identified miR-130b as a potential target of mutant p53. Ectopic expression of p53 mutants repressed the expression of miR-130b and triggered ZEB1-dependent EMT and cancer cell invasion. Loss of an endogenous p53 mutation increased the expression of miR-130b, which resulted in reduced ZEB1 expression and attenuation of the EMT phenotype. Furthermore, re-expression of miR-130b suppressed mutant p53-induced EMT and ZEB1 expression. Importantly, the expression of miR-130 was significantly reduced in EC tissues, and patients with higher expression levels of miR-130b survived longer. These data provide a novel understanding of the roles of p53 gain-of-function mutations in accelerating tumor progression and metastasis through modulation of the miR-130b–ZEB1 axis.

BACKGROUND The incidence and distribution pattern of retroperitoneal lymph node metastasis in patients with cervical carcinoma should be investigated based on data from systematic pelvic lymph node (PLN) and paraaortic lymph node (PAN) dissection, so that a basis can be established for determining the site of selective lymph node dissection or sampling. METHODS A total of 208 patients with Stages IB, IIA, and IIB cervical carcinoma who underwent radical hysterectomy and systematic pelvic and PAN dissection were investigated for lymph node metastasis and histopathologic risk factors for lymph node metastasis. RESULTS Fifty‐three patients (25.5%) had lymph node metastasis. The obturator lymph nodes were most frequently involved, with a rate of 18.8% (39/208). Forty‐nine of 53 node‐positive patients had lymph node metastasis in the obturator, internal iliac, or common iliac lymph nodes. Of 26 solitary lymph node metastases confined to one node group, 18 were in the obturator, 3 in the internal iliac, 3 in the parametrial, and 2 in the common iliac lymph nodes. A multiple logistic regression analysis revealed that deep cervical stromal invasion and lymph‐vascular space invasion were related to PLN metastasis. It was also shown that metastasis to bilateral PLNs (excluding the common iliac lymph nodes) as well as metastasis to the common iliac lymph nodes were significantly related to PAN metastasis. CONCLUSIONS The results of this study suggest that the obturator lymph nodes can be sentinel lymph nodes of cervical carcinoma. PAN metastasis appears to occur secondarily to wide‐spread PLN metastasis. These results provide a basis for determining the site of selective lymph node dissection and for estimating the existence of PAN metastasis from the pattern of metastasis in PLN in patients with cervical carcinoma. Cancer 1999;85:1547–54. © 1999 American Cancer Society.

BackgroundEpithelial-mesenchymal transition (EMT) is the key process driving cancer metastasis. Oncogene/self renewal factor BMI-1 has been shown to induce EMT in cancer cells. Recent studies have implied that noncoding microRNAs (miRNAs) act as crucial modulators for EMT. The aims of this study was to determine the roles of BMI-1 in inducing EMT of endometrial cancer (EC) cells and the possible role of miRNA in controlling BMI-1 expression.Methods and resultsWe evaluated the expression of BMI-1 gene in a panel of EC cell lines, and detected a strong association with invasive capability. Stable silencing of BMI-1 in invasive mesenchymal-type EC cells up-regulated the epithelial marker E-cadherin, down-regulated mesenchymal marker Vimentin, and significantly reduced cell invasion in vitro. Furthermore, we discovered that the expression of BMI-1 was suppressed by miR-194 via direct binding to the BMI-1 3'-untranslated region 3'-UTR). Ectopic expression of miR-194 in EC cells induced a mesenchymal to epithelial transition (MET) by restoring E-cadherin, reducing Vimentin expression, and inhibiting cell invasion in vitro. Moreover, BMI-1 knockdown inhibited in vitro EC cell proliferation and clone growth, correlated with either increased p16 expression or decreased expression of stem cell and chemoresistance markers (SOX-2, KLF4 and MRP-1).ConclusionThese findings demonstrate the novel mechanism for BMI-1 in contributing to EC cell invasion and that repression of BMI-1 by miR-194 could have a therapeutic potential to suppress EC metastasis.

To examine the association between colonization by two newly classified species of genital ureaplasmas (Ureaplasma parvum and U. urealyticum) in early pregnancy and subsequent late abortion or preterm birth at <34 weeks of gestation, four species of genital mycoplasmas-Mycoplasma genitalium, M. hominis, U. parvum, and U. urealyticum-as well as Chlamydia trachomatis and Neisseria gonorrhoeae were examined by PCR-based methods in a prospective cohort study of 877 women with singleton pregnancies at <11 weeks of gestation. Antibiotics were used only in cases in which C. trachomatis and/or N. gonorrhoeae was detected. Multivariate logistic-regression analysis was used to assess independent risk factors after taking maternal low body weight and past history of preterm birth into account. M. genitalium, M. hominis, U. parvum, U. urealyticum, C. trachomatis, and N. gonorrhoeae were detected in 0.8%, 11.2%, 52.0%, 8.7%, 3.2%, and 0.1% of these 877 women, respectively. Twenty-one (2.4%) women experienced late abortion or preterm birth at <34 weeks of gestation. Preterm birth and low birth weight are the leading causes of neonatal mortality and morbidity in the developed world. More than 60% of the mortality among infants without anatomic or chromosomal defects can be attributed to low birth weight (20). Ascending genital tract infections contribute to up to 50% of premature deliveries, particularly those occurring before 30 weeks of gestation (4, 15). Moreover, the rate of neonatal complications has been shown to be higher in neonates born to women with microbial invasion of the amniotic cavity than born to those women without infection (10).Genital mycoplasmas, including Mycoplasma hominis, M. genitalium, and Ureaplasma spp., are suspected of contributing to a number of pathological conditions. M. hominis was isolated from the amniotic fluid in 30% of 404 women with intraamniotic infection (21) and was shown to be associated with preterm birth at Ͻ33 weeks of gestation (23). M. genitalium was suggested to cause urethritis in men (11) and mucopurulent cervicitis in women (16), but its association with preterm birth has not been studied extensively. Ureaplasma has been implicated in infertility, spontaneous abortion, stillbirth, premature birth, low birth weight, and perinatal morbidity and mortality (3). Vaginal colonization with Ureaplasma has not been associated with preterm birth (3), while the presence of Ureaplasma in the amniotic fluid is associated with a robust host response in fetal, amniotic, and maternal compartments (24) and subsequent preterm birth (7). It is not known why this microorganism invades the amniotic cavity only in some women despite heavy colonization of the vagina by Ureaplasma.Recently, the species previously classified as Ureaplasma urealyticum was separated into two new species: U. parvum (previously U. urealyticum biovar 1) and U. urealyticum (previously U. urealyticum biovar 2) (14, 19). Therefore, U. urealyticum organisms examined in previous studies (3, 7, 24) may have included both U. p...

A surgical specimen was obtained from a patient (female, 73 years old) who was diagnosed with lung adenocarcinoma (mixed subtypes) and underwent pulmonary lobe resection at the Department of Cardiovascular and Thoracic Surgery, Hokkaido University Hospital in 2015. The patient did not undergo any preoperative chemotherapy or radiotherapy. The resected lung cancer tissues (~1.0 cm 3 without necrosis) were put into ice-cold RPMI-1640 supplemented with 10% fetal bovine serum (HyClone, GE Healthcare), 0.1 mM non-essential amino acids (Gibco), 100 IU/ml penicillin and 100 μg/ml streptomycin (Gibco) and 0.03% glutamine (Gibco), and transported immediately to the lab. After the removal of blood clots, the sample was rinsed with sterile PBS and cut into small fragments (~1 mm 3

MicroRNA-101 has been implicated as a tumor suppressor miRNA in human tumors. However, its potential functional impact and the underlying mechanisms in endometrial cancer progression have not been determined. Here, we report that in aggressive endometrial cancer cells, re-expression of microRNA-101 leads to inhibition of cell proliferation and induction of apoptosis and senescence. Ectopic overexpression of microRNA-101 attenuates the epithelial-mesenchymal transition-associated cancer cell migration and invasion, abrogates the sphere-forming capacity and enhances chemosensitivity to paclitaxel. Algorithm and microarray-based strategies identifies potential microRNA-101 targets. Among these, we validated EZH2, MCL-1 and FOS as direct targets of miR-101 and silencing of these genes mimics the tumor suppressive effects observed on promoting microRNA-101 function. Importantly, further results suggest an inverse correlation between low miR-101 and high EZH2, MCL-1 and FOS expression in EC specimens. We conclude that, as a crucial tumor suppressor, microRNA-101 suppresses cell proliferation, invasiveness and self-renewal in aggressive endometrial cancer cells via modulating multiple critical oncogenes. The microRNA-101-EZH2/MCL-1/FOS axis is a potential therapeutic target for endometrial cancer.