Heterochromatin Protein 1γ Epigenetically Regulates Cell Differentiation and Exhibits Potential as a Therapeutic Target for Various Types of Cancers

Heterochromatin protein 1 (HP1) is a chromosomal protein that participates in both chromatin packaging and gene silencing. Three HP1 isoforms (α, β, and γ) occur in mammals, but their functional differences are still incompletely understood. In this study, we found that HP1γ levels are decreased during adipocyte differentiation, whereas HP1α and β levels are expressed constitutively during adipogenesis in cultured preadipocyte cells. In addition, ectopic overexpression of HP1γ inhibited adipogenesis. Furthermore, we did not detect any HP1γ protein in the differentiated cells of various normal human tissues. These results suggest that the loss of HP1γ is required for cell differentiation to occur. On the other hand, the methylation levels of lysine 20 (K20) on histone H4 showed a significant correlation with HP1γ expression in both these preadipocyte cells and normal tissue samples. However, all cancer tissues examined were positive for HP1γ but were often negative for trimethylated histone H4 K20. Thus, a dissociation of the correlation between HP1γ expression and histone H4 K20 trimethylation may reflect the malfunction of epigenetic control. Finally, suppression of HP1γ expression restrained cell growth in various cancer-derived cell lines, suggesting that HP1γ may be an effective target for gene therapy against various human cancers. Taken together, our results demonstrate the novel function of HP1γ in the epigenetic regulation of both cell differentiation and cancer development.     

A case of colon cancer with long-term survival treated by resection of recurrence on the rectum and chemotherapy for lung metastasis

A 69-year-old male was operated on sigmoidectomy for sigmoid colon cancer (SS, N2, H0, P0, M0, stage IIIb) 7 years ago. Two years later, he was diagnosed for rectal cancer and bilateral lung metastases by TBLB. We performed Mile's operation, and the rectal focus was pathologically diagnosed with a recurrence of sigmoid colon cancer. After surgery, chemotherapy with FOLFOX was started for bilateral lung metastases, resulting in CR during the 22 months. But bilateral lung metastases were exacerbated, and then we administered several other chemotherapies. Five years have passed since chemotherapy started, although the focuses tended to progress. Right now, he has been a chemotherapy outpatient for last 5 years.     

Effective treatment by both anti-androgen therapy and chemotherapy for a patient with advanced salivary duct carcinoma

Salivary ductcarcinoma (SDC)is a high-grade malignant tumor arising predominantly in the parotid gland. Androgen receptor(AR)expression was mainly restricted to SDC in salivary cancer. We report successful treatment of a patient with advanced SDC using an endocrine chemotherapy. A 76-year-old man was hospitalized with lumbalgia and swelling of left submandibular region. Radiological examination indicated a tumor in left submandibular gland and metastatic tumors in lumbar vertebra, accompanied by swollen lymph nodes of the neck, mediastinum. Needle biopsies of both vertebral tumor and cervical lymph node revealed SDC. Positive nuclear staining was observed against AR in tumor cells of our patient by immunohistochemical analysis. He obtained a partial response after 1 course of treatment with both anti-androgen therapy and palliative chemotherapy using paclitaxel. In contrast to previous reports of poor response to chemotherapy alone and short-term survival of patients with SDC, our patient has demonstrated that chemotherapy combined with anti-androgen therapy may be an effective modality as a therapeutic regimen for SDC.     

A case of the long-term survivor of rectal cancer who suffered from successive metastases to ovarium, peritoneum, liver, bone and para-aortic lymphonode

A 37-year-old female, who had undergone a low anterior resection for lower rectal cancer, had been received chemotherapy (FOLFOX4, FOLFIRI) for 2 years because of right ovarian metastasis occurred and removed 9 months after the first operation. One month after 2 years of continued chemotherapy, progressive metastases happened to occur successively (rt lunge, left ovarium, liver, para-aortic lymphonode, Virchow lymphonode and bone). Right upper lobe pnemonectomy was performed first, then, peritonectomy, total hysterectomy with left oophorectomy and a partial resection of the small bowel were done. IRIS, as postoperative chemotherapy, performed with hepatic arterial infusion (HAI) of CPT-11 and 5- FU resulted in getting a minimal response for about 10 months. Because of the hepatic arterial thrombosis at 10 months after the previous operation, we could not continue HAI with systemic chemotherapy, that was resulted in the progresion of mutiple metastases, and that the patient died 62 months after the first surgery. Immunohistochemical analyses with MIB-1 stainning of four surgical specimens revealed 80% positive cells in the cancerous tissues.     

A case of adenocarcinoma of the esophagogastric junction successfully treated with chemoradiation therapy

The patient was an 80-year-old female with chief complaint of anemia. She was diagnosed as a type 3 gastric cancer (por/tub2) of the esophagogastric junction by gastrointestinal endoscopy in November 2010. CT scan revealed no distant metastasis and we diagnosed as c-stage II B (T4aN0M0). However, severe COPD was detected by the respiratory function test. Considering her age and respiratory function, we decided that total gastrectomy under general anesthesia was difficult. She was treated with radiation( 50.4 Gy/28 Fr) and the combination chemotherapy of S-1( 80 mg/m2, day 1-21) plus low-dose CDDP (6 mg/m2, day 1-5, 8-12, 15-19) during her hospitalization, and treated with S-1 mono-therapy as an outpatient. The tumor was reduced and the hemorrhage was not seen though the response was SD. Moreover, she did not experience any adverse event of grade 3 or more. The chemoradiation therapy appears to be effective for patients of adenocarcinoma of the esophagogastric junction.     

Effect of polymorphisms of IL-1β and TNF-α genes on CpG island hyper methylation (CIHM) in the nonneoplastic gastric mucosa

CpG island hyper methylation (CIHM) is one of the major events in gastric carcinogenesis. To evaluate the influence of host genetic factors in CIHM related carcinogenesis, we investigated the association between common polymorphisms in IL-1β and TNF-α genes, with CIHM status in the nonneoplastic gastric mucosa. Polymorphisms in the IL-1β gene (-31T>C and -511C>T) and the TNF-α gene (-857C>T) were genotyped in 385 cancer-free subjects. CIHM of four candidate genes: p16 (INK4a), p14 (ARF), E-cadherin (CDH1), and death-associated protein kinase (DAP-kinase), were determined by methylation-specific-polymerase chain reaction (MSP). CIHM high was defined as two or more CpG islands methylated. CIHM of all four genes and CIHM high were significantly associated with Helicobacter pylori infection status. In over all, significant marginal association was found between IL-1β-511 TT genotype and reduced susceptibility to CIHM of DAP-kinase (adjusted OR = 0.48, 95% CI = 0.29-0.78) and CIHM high (adjusted OR = 0.53, 95% CI = 0.32-0.86). This association was more enhanced in subjects 65 yr or younger age. We also found positive association between TNF-α-857T carrier and increased susceptibility to CIHM of CDH (adjusted OR = 1.78, 95% CI = 1.01-3.16), and CIHM high (adjusted OR = 1.86, 95% CI = 1.04-3.33) in the same generation. The mean number of CIHM was lower in subjects with IL-1β-511TT genotype, while the mean number was higher in subjects with TNF-α-857 T carrier especially in subjects 65 yr and younger patients. IL-1β-511 TT genotype is associated with reduced susceptibility to CIHM especially in younger generation. Furthermore, the TNF-α-857T carrier is associated with increased susceptibility of CIHM in the same generation.     

Site-specificity of mineral ions in 2-day dental plaque obtained from children and young adults

The aim of this study was to determine the variation in mineral ions (Ca and P) concentrations in 2-day dental plaque taken from different areas of the deciduous and the permanent dentition that may be related to the caries status of tooth surfaces obtained from children and young adults. We also compared those minerals between the deciduous and the permanent dentition. Plaque samples were collected from eight dentition sites, including the upper-anterior-buccal (UAB) and -lingual (UAL), lower-anterior-buccal (LAB) and -lingual (LAL), upper-posterior-buccal (UPB) and -lingual (UPL), lower-posterior-buccal (LPB) and -lingual (LPL) regions. Significant differences among these eight different sites were determined from Ca and P ions concentrations, as well as the Ca/P ratio, calculated by ANOVA. Plaque associated with the LAL region closest to the main salivary ducts and that is less prone to caries, had significantly higher levels of Ca, P ions concentrations, a higher Ca/P ratio than any other dentition areas in both children and young adult subjects. Statistical differences were seen in minerals between children and young adults. Ca ion concentrations in dental plaque from young adults were significantly higher than those of children at the LAL site. Statistical analysis of the relationships between Ca and P ions showed that there were strong associations between Ca and P ions, especially in the UPB, LAL and LPL regions where there is a high exposure to saliva. We conclude that there is a site-specificity of plaque mineral content in both children and young adults, which may reflect the differences in exposure to saliva, resulting in differences in the local cariostatic challenge.