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SOX9 has been previously shown to be involved in hepatocellular carcinoma (HCC) and other types of cancer. However, prognostic studies so far involved rather small cohorts or lack external validation and experimental data. In this study, we firstly determined the histological expression pattern of SOX9 in human HCC by immunohistochemistry (n = 84) and evaluated its prognostic value. External cohorts of publicly available datasets were used to validate its prognostic relevance in HCC (n = 359) and other types of cancer including breast (n = 3951), ovarian (n = 1306), lung (n = 1926) and gastric cancer (n = 876). Functional SOX9 knock-down studies using siRNA and cancer stem cell models were generated in a panel of liver and breast cancer cell lines. High level of SOX9 was associated with poor survival even after adjustment for other prognostic factors in multivariate analysis (HR = 2.103, 95%CI = 1.064 to 4.156, p = 0.021). SOX9 prevailed a poor prognostic factor in all cancer validation cohorts (p<0.05). Reduced SOX9 expression by siRNA decreased the growth of liver cancer cells (p<0.05). SOX9 expression was associated with stem cell features in all tested cell lines (p<0.05). In conclusion, this study demonstrated in a large number of patients from multiple cohorts that high levels of SOX9 are a consistent negative prognostic factor.

Recently, a novel mechanism introducing genetic instability, termed aberrant somatic hypermutation (ASHM), has been described in diffuse large B-cell lymphoma. To further investigate whether ASHM also occurs in mucosa-associated lymphoid tissue type (MALT) lymphoma, we studied the mutation profile of PIM1, IntroductionExtranodal marginal zone B-cell lymphoma of the mucosaassociated lymphoid tissue type (MALT lymphoma) preferentially arises in the gastrointestinal tract, especially the stomach where it is closely linked to a Helicobacter pylori-induced chronic gastritis. 1,2 In general, MALT lymphoma may affect virtually every organ in the body. 3,4 Because of the interaction between lymphoma cells and mucosal adhesion molecules, 5 MALT lymphomas display an indolent clinical behavior; however, transformation in diffuse large B-cell lymphoma (DLBCL) occurs but, according to the WHO criteria, is considered as a separate entity. 6 Foci of extranodal DLBCL may be seen in MALT lymphoma, termed transformed MALT lymphoma, suggestive of transformation from one to the other entity.MALT lymphomas demonstrate a number of distinct cytogenetic alterations, 7 but a molecular mechanism inducing genetic instability has not been described. In DLBCL somatic hypermutation aberrantly targets the 5Ј sequences of several protooncogenes relevant to lymphomagenesis, including PIM1, PAX5, RhoH/TTF, and cMYC. This phenomenon, termed aberrant somatic hypermutation (ASHM) occurs in over 50% of DLBCL but is rare in indolent lymphomas. 8 Although the molecular mechanism of the SHM is still unknown, studies identified the activation-induced cytidine deaminase (AID) as an absolute requirement for the SHM. 9 The present study was aimed at investigating the role of the aberrant somatic hypermutation in MALT lymphomas and in MALT lymphomas transformed to extranodal DLBCL and to elucidate the role of AID in this process. Materials and methods Materials, diagnoses, and DNA extractionDNA extraction (DNA Mini Kit; Qiagen, Valencia, CA) was performed from formalin-fixed and paraffin-embedded macrodissected tissue containing at least 90% malignant cells. Seventeen MALT lymphoma specimens, 6 of gastric origin and 11 of extragastric origin (2 orbita, 7 parotid gland, 1 thyroid, and 1 soft tissue), and 17 samples of extranodal DLBCL, 10 of gastric origin and 7 of extragastric origin (2 thyroid and 5 parotid gland), and 6 normal controls, including 5 surrounding nonneoplastic tissues samples and one of peripheral blood mononuclear cells were included. All lymphomas were classified according to the WHO classification of lymphoid neoplasms. 6 Attention was made that cases of extranodal DLBCL comprised at least one focus of a low-grade lymphoma component considering these lymphomas as "transformed MALT lymphomas." 10 Immunohistochemistry was performed using monoclonal antibodies to The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate ...

Chemokine receptors mediate migration and activation of lymphocytes through binding of their ligands. Recent studies have revealed important contributions of chemokine receptors to the development, progression, and dissemination of haematopoietic neoplasms. Because the chemokine receptor expression profile in extragastric MALT lymphoma is unknown, we performed a comprehensive study on tissue samples of parotid glands, parotid glands affected by Sjögren syndrome, extragastric MALT lymphoma, and extranodal diffuse large B-cell lymphoma (eDLBCL) originating from MALT lymphoma (transformed MALT lymphoma). By investigating the expression of 19 chemokine receptors by real-time PCR using a semi-quantitative approach and of four chemokine receptors (CCR1, CCR5, CXCR6, and XCR1) by immunohistochemistry, we show that the chemokine receptor expression profiles of extragastric MALT lymphomas differ substantially from those of extranodal DBLCL, with lower expression of CCR1, CCR8, and CXCR3, and the absence of expression of CX3CR1 and XCR1 in eDLBCL. Expression of CCR6, CCR7, CXCR3, CXCR4, and CXCR5, responsible for B-cell homing to secondary lymphoid tissue, was detected in both B-cell malignancies. Expression of CCR4 was just detected in trisomy 3-positive MALT lymphoma cases. Comparing gastric with extragastric MALT lymphomas, up-regulation of CXCR1 and CXCR2 accompanied by down-regulation of CCR8 and CX3CR1 and loss of XCR1 expression in extragastric MALT lymphomas appear to be key determinants for the site of origin of MALT lymphomagenesis. Our results support a model of stepwise progression of extragastric MALT lymphoma from a non-neoplastic event to Sjögren syndrome, to MALT lymphoma, and finally to overt eDLBCL, guided by differentially expressed B-cell homeostatic and activation-dependent chemokine receptors and their ligands.