Ribosomal S6 protein kinase 4 promotes radioresistance in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive cancers and is highly resistant to current treatments. ESCC harbors a subpopulation of cells exhibiting cancer stem-like cell (CSC) properties that contribute to therapeutic resistance including radioresistance, but the molecular mechanisms in ESCC CSCs are currently unknown. Here, we report that ribosomal S6 protein kinase 4 (RSK4) plays a pivotal role in promoting CSC properties and radioresistance in ESCC. RSK4 was highly expressed in ESCC CSCs and associated with radioresistance and poor survival in patients with ESCC. RSK4 was found to be a direct downstream transcriptional target of ΔNp63α, the main p63 isoform, which is frequently amplified in ESCC. RSK4 activated the ß-catenin signaling pathway through direct phosphorylation of GSK-3ß at Ser9. Pharmacologic inhibition of RSK4 effectively reduced CSC properties and improved radiosensitivity in both nude mouse and patient-derived xenograft models. Collectively, our results strongly suggest that the ΔNp63α/RSK4/GSK-3ß axis plays a key role in driving CSC properties and radioresistance in ESCC, indicating that RSK4 is a promising therapeutic target for ESCC treatment.

Activation of the NF-κB Pathway and Heterozygous Deletion of TNFAIP3 (A20) Confer Superior Survival in Extranodal Natural Killer/T-Cell Lymphoma, Nasal Type.

OBJECTIVES: To investigate the role of TNFAIP3 deletions and NF-κB activation in extranodal natural killer/T-cell lymphoma (ENKTCL), nasal type. METHODS: In total, 138 patients with ENKTCL were included. Activation of NF-κB pathway and expression of TNFAIP3 (A20) were examined by immunohistochemistry. TNFAIP3 was analyzed for deletions using FICTION (fluorescence immunophenotyping and interphase cytogenetics as a tool for investigating neoplasms), for mutations using Sanger sequencing, and for promoter methylation using methylation-specific sequencing. RESULTS: NF-κB pathway activation was observed in 31.2% of cases (43/138), TNFAIP3 expression was negative in 15.2% of cases (21/138), and heterozygous TNFAIP3 deletion was observed in 35% of cases (35/100). TNFAIP3 exons 2 to 9 mutations and promoter methylation were not observed. Kaplan-Meier analysis showed patients with NF-κB pathway activation or TNFAIP3 heterozygous deletion to have a longer overall survival. CONCLUSIONS: Our study demonstrated that NF-κB activation and TNFAIP3 heterozygous deletion confer superior survival in patients with ENKTCL.

Resistance to apoptosis should not be taken as a hallmark of cancer.

In the research community, resistance to apoptosis is often considered a hallmark of cancer. However, pathologists who diagnose cancer via microscope often see the opposite. Indeed, increased apoptosis and mitosis are usually observed simultaneously in cancerous lesions. Studies have shown that increased apoptosis is associated with cancer aggressiveness and poor clinical outcome. Furthermore, overexpression of Bcl-2, an antiapoptotic protein, is linked with better survival of cancer patients. Conversely, Bax, CD95, Caspase-3, and other apoptosis-inducing proteins have been found to promote carcinogenesis. This notion of the role of apoptosis in cancer is not new; cancer cells were found to be short-lived 88 years ago. Given these observations, resistance to apoptosis should not be considered a hallmark of cancer.

Invasive cancers are not necessarily from preformed in situ tumours - an alternative way of carcinogenesis from misplaced stem cells.

Cancers are thought to be the result of accumulated gene mutations in cells. Carcinomas, which are cancers arising from epithelial tissues usually go through several stages of development: atypical hyperplasia, carcinoma in situ and then invasive carcinoma, which might further metastasize. However, we think that the present pathological data are enough to prove that there might be an alternative way of carcinogenesis. We propose that majority of invasive cancers arise in the connective tissue stroma de novo, from the misplaced epithelial stem cells which come to the wrong land of connective tissue stroma by accident. The in situ carcinomas, which are mostly curable, should not be considered genuine cancer, but rather as quasi-cancer. We design this new theory of carcinogenesis as the stem cell misplacement theory (SCMT). Our SCMT theory chains together other carcinogenesis theories such as the inflammation-cancer chain, the stem cell theory and the tissue organization field theory. However, we deny the pathway of somatic mutation theory as the major pathway of carcinogenesis.

Rectal carcinoma metastatic to the male breast after 7 years: case report.

BACKGROUND: Colorectal cancer metastasis to a mammary location is very rare. CASE REPORT: A 38-year-old male, who had undergone anterior resection of an advanced rectal carcinoma 7 years earlier, presented with a right mammary mass. Core needle biopsy of the mass indicated cytology consistent with breast adenocarcinoma. After neoadjuvant chemotherapy and modified radical mastectomy, pathology identified the mass as rectal carcinoma. CONCLUSION: The authors highlight the difficulty of making an accurate diagnosis of rectal cancer metastasis to the breast of a male.

Overexpression of CYP2E1 enhances sensitivity of hepG2 cells to fas-mediated cytotoxicity.

Hepatocellular carcinoma (HCC) has been reported to be resistant to Fas-mediated apoptosis. In present study, experiments were conducted to investigate the potential effects of CYP2E1 overexpression on susceptibility of HCC to Fas-mediated cytotoxicity. HCC cell line HepG2 was infected with Ad-CYP2E1 to enhance the expression of CYP2E1, followed by treatment with low toxic dose of recombinant human Fas ligand (FasL, 0.5 ng/ml) in the presence of Actinomycin D (Act D, 125 ng/ml). High level of Fas expression was found in HepG2 cells. Its protein level and distribution kept unchanged after different treatments. Compared with control, CYP2E1 expressed HepG2 cells were more sensitive to FasL plus Act D. The sensitivity was elevated in a multiplicity of infection (m.o.i)-dependent manner, which was dramatically suppressed by CYP2E1 inhibitor diallyl disulfide (DAS) (p < 0.01). The percentage of apoptotic cells caused by FasL/Act D was increased from 18.7 to 75% after infection with Ad-CYP2E1 (p < 0.01). DAS treatment resulted in 60% reduction of apoptotic ratio (p < 0.01). Antioxidants GSH ethyl ester, Vitamin C and Vitamin E efficiently protected against cytotoxicity induced by FasL plus Act D in CYP2E1-expressed HepG2 cells. After adding FasL/Act D, increased caspases activities, lipid preoxidation and reduced GSH level, as well as mitochondrial release of cytochrome c were found in Ad-CYP2E1 infected cells (all p < 0.01); these changes were significantly attenuated by DAS (all p < 0.05). These results suggested that CYP2E1 potentiates Fas-mediated HepG2 cells toxicity via the induction of oxidative stress to promote apoptosis. Adenovirus-mediated overexpresson of CYP2E1 may have an important role in the elimination of hepatoma cells mediated by immune effector cells in the liver.