Genomic studies have improved our understanding of the biological basis of splenic (SMZL) and nodal (NMZL) marginal zone lymphoma by providing a comprehensive and unbiased view of the genes/pathways that are deregulated in these diseases. Consistent with the physiological involvement of NOTCH, NF-κB, B-cell receptor and toll-like receptor signaling in mature B-cells differentiation into the marginal zone B-cells, many oncogenic mutations of genes involved in these pathways have been identified in SMZL and NMZL. Beside genetic lesions, also epigenetic and post-transcriptional modifications contribute to the deregulation of marginal zone B-cell differentiation pathways in SMZL and NMZL. This review describes the progress in understanding the molecular mechanism underlying SMZL and NMZL, including molecular and post-transcriptional modifications, and discusses how information gained from these efforts has provided new insights on potential targets of diagnostic, prognostic and therapeutic relevance in SMZL and NMZL.

Promoter DNA methylation is a major regulator of gene expression and transcription. The identification of methylation changes is important for understanding disease pathogenesis, for identifying prognostic markers and can drive novel therapeutic approaches. In this review we summarize the current knowledge regarding DNA methylation in MALT lymphoma, splenic marginal zone lymphoma, nodal marginal zone lymphoma. Despite important differences in the study design for different publications and the existence of a sole large and genome-wide methylation study for splenic marginal zone lymphoma, it is clear that DNA methylation plays an important role in marginal zone lymphomas, in which it contributes to the inactivation of tumor suppressors but also to the expression of genes sustaining tumor cell survival and proliferation. Existing preclinical data provide the rationale to target the methylation machinery in these disorders.

Marginal zone lymphomas (MZL) are a diverse group of indolent lymphoproliferative disorders that comprise three subtypes: nodal, splenic and mucosal associated marginal zone lymphomas (MALT). Histologic transformation (HT) to an aggressive lymphoma is a rare event that can occur in any subtype, and at lower frequency compared to other indolent non Hodgkin lymphomas (NHL) like follicular lymphoma. There are few data directly associated with risk and prognosis of transformation in MZL. However, recent advances in the understanding of molecular and genetic features of MALT have contributed to an evolving appreciation of HT in this disease. Optimal treatment of HT of MZL remains unknown. Much of the approach to managing transformed MZL is extrapolated from other indolent NHLs.

Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) occurs at diverse anatomic sites and is closely associated with several distinct chronic inflammatory disorders. Both the acquired genetic abnormalities and active chronic immunological responses play a critical role in the development of MALT lymphoma, interestingly by dysregulating similar molecular mechanisms. The three translocations seen in MALT lymphoma, namely t(14;18)(q32;q21)/IGH-MALT1, t(1;14)(p22;q32)/BCL10-IGH, and t(11;18)(q21;q21)/BIRC3 (API2)-MALT1 are capable of activating both canonical and non-canonical NF-κB pathways. TNFAIP3 (A20) inactivation by deletion and/or mutation abolishes its negative regulation to several signalling including BCR and TLR, which activate the canonical NF-κB pathway. Similarly, the immunological responses also activate the canonical NF-κB pathway via surface antigen receptor and TLR, and the non-canonical NF-κB pathway by T-cell help and BAFFR. There is also emerging evidence indicating oncogenic cooperation between the above genetic changes and immunological stimulation in the pathogenesis of MALT lymphoma.

The use of saliva as a diagnostic fluid enables non-invasive sampling and thus is a prospective sample for disease tests. This study fully utilized the information from the salivary transcriptome to characterize pancreatic cancer related genes and predict novel salivary biomarkers.

The gene solute carrier family 34 (sodium phosphate), member 2 (SLC34A2), is a member of the SLC34 family. Increasing evidence suggests that SLC34A2 is involved in the development of many human carcinomas. However, its role in hepatocellular carcinoma (HCC) is still unclear. Therefore, in this study we investigated the role of SLC34A2 in HCC and explored the underlying mechanism. We found that the expression of SLC34A2 is upregulated in HCC cell lines. Knockdown of SLC34A2 obviously inhibited HCC cell proliferation, migration/invasion, and the epithelial-mesenchymal transition (EMT) phenotype. Furthermore, knockdown of SLC34A2 significantly inhibited the expression of phosphorylated PI3K and AKT in HCC cells. Taken together, these results suggest that knockdown of SLC34A2 inhibits proliferation and migration by suppressing activation of the PI3K/AKT signaling pathway in HCC cells, and SLC34A2 may be a potential therapeutic target for the treatment of HCC.

Hepatocellular carcinoma (HCC) is one of the most common malignancies, with a poor prognosis and high recurrence rate. In the present study, we identified CD133, one of the markers of cancer stem cells, as a novel molecular target of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). In four human HCC cell lines established from primary HCC tumors, we found that CD133-high human liver cancer stem-like cells (CD133hi) derived from the SNU-475 cell line were highly susceptible to TRAIL compared to other HCC cell lines with a small population of CD133. CD133hi SNU-475 cells showed upregulation of TRAIL receptor DR5 and stemness-related genes such as c-Myc and ABC transporters compared to their CD133-low (CD133lo) cells. Hypersensitivity of CD133hi cells to TRAIL was associated with c-Myc-mediated upregulation of DR5 and downregulation of c-FLIPL in the cells. Knockdown of CD133 expression in CD133hi cells resulted in the downregulation of c-Myc, and depletion of c-Myc caused a decrease in the cell surface expression of DR5 and an increase in the expression of c-FLIPL and, consequently, attenuated TRAIL-induced cytotoxicity and apoptosis of CD133hi cells. These results suggest that TRAIL may provide a new strategy for CD133hi CSCs of HCC-targeted therapies and, potentially, for therapies of other CD133-expressing types of cancer.

This study aimed to investigate the pivotal role of cystatin B (CSTB) in the development of gastric cancer and to explore its possible regulatory mechanism. Human gastric cancer SGC-7901 cells as a model in vitro were transfected with plasmid PCDNA3.1-CSTB and siRNA-CSTB using Lipofectamine 2000. Quantitative real-time PCR (qRT-PCR) and Western blotting were performed to determine the relative expression of CSTB and PI3K/Akt/mTOR pathway-related protein. Moreover, MTT assay, Transwell assay, and flow cytometry were used to assess cell proliferation, migration, and apoptosis, respectively. The results showed that CSTB was significantly downregulated in SGC-7901 cells compared with gastric epithelial cells. CSTB was successfully overexpressed and suppressed after cells were transfected with pc-CSTB and si-CSTB, respectively. Moreover, cell viability and migration were significantly decreased after being transfected with pc-CSTB when compared with the control group, while being obviously increased after transfection with si-CSTB. However, cell apoptosis was significantly induced after being transfected with pc-CSTB, while being obviously suppressed after transfection with si-CSTB. Besides, the expression levels of p-PI3K, p-Akt, and p-mTOR proteins were all significantly decreased in the pc-CSTB transfection group when compared with the control group, while being increased in the si-CSTB transfection group. Our findings suggest that CSTB downregulation may promote the development of gastric cancer by affecting cell proliferation and migration, and the PI3K/Akt/mTOR signaling pathway was activated in this process. CSTB may serve as a potential therapeutic target for gastric cancer.

Collagen triple helix repeat containing-1 (CTHRC1), a secreted glycoprotein, is frequently upregulated in human cancers. However, the functional role of CTHRC1 in renal cell carcinoma (RCC) remains unclear. Thus, the aim of this study was to explore the role of CTHRC1 in RCC. Our results demonstrated that CTHRC1 was upregulated in RCC tissues and cell lines. Knockdown of CTHRC1 significantly inhibits the proliferation in RCCs. Furthermore, knockdown of CTHRC1 significantly inhibited the epithelial-to-mesenchymal transition (EMT) process in RCCs, as well as suppressed RCC cell migration and invasion. Mechanistically, knockdown of CTHRC1 inhibited the expression of β-catenin, c-Myc, and cyclin D1 in RCC cells. In conclusion, the results of the present study indicated that CTHRC1 downregulation inhibited proliferation, migration, EMT, and β-catenin expression in RCC cells. Therefore, CTHRC1 may be a potential therapeutic target for the treatment of RCC.

Pyruvate kinase (PK) is a key enzyme in the process of glycolysis, catalyzing phosphoenolpyruvate (PEP) into pyruvate. Currently, PK isozyme type M2 (PKM2), one subtype of PK, has been proposed as a new tumor marker with high expression in various tumor tissues. Here we aimed to explore the effects of siRNA-PKM2 on ovarian carcinoma (OC) cell lines SKOV3 and OVCAR3, in which PKM2 was notably expressed. PKM2 gene interference lentivirus vectors were built by miRNA transfection assay. siRNA-PKM2-transfected SKOV3 and OVCAR3 cells were evaluated for cell proliferation, cell cycle distribution, cell apoptosis, cell migration, and invasion in this study. In addition, the expression levels of several tumor-related genes were measured using real-time PCR and Western blot. Results showed that siRNA-PKM2 markedly inhibited cell proliferation, induced apoptosis, and caused cell cycle arrest at the G0/G1 phase. Cell migration and invasion were significantly suppressed by siRNA-PKM2. Furthermore, the tumor-related genes caspase 7, Bad, and E-cadherin were upregulated, while MMP2, HIF1α, VEGF, and MMP9 were depressed by siRNA-PKM2. The function of siRNA-PKM2 on the biological behavior of OC cells indicated that PKM2 may also be a target for treatment of OC.

Breast cancer is a highly prevalent disease affecting women. The association of IQ motif containing GTPase-activating protein 3 (IQGAP3) and breast cancer is poorly defined. Here we reported that IQGAP3 is a key regulator of cell proliferation and metastasis during breast cancer progression. The expression of IQGAP3 was significantly increased in breast tissues compared to nontumor tissues at both protein and mRNA levels. Furthermore, IQGAP3 had a high expression level in ZR-75-30 and BT474 compared to other breast cancer cell lines. Depletion of IQGAP3 through RNA interference in ZR-75-30 and BT474 significantly inhibited cell proliferation. More importantly, IQGAP3 silencing in breast cancer cells notably repressed cell migration and invasion. Further analysis suggested that inhibition of cell proliferation and metastasis was associated with some proteins, including p53, MMP9, Snail, CDC42, p-ERK1/2, KIF2C, KIF4A, PCNA, and Twist. Since expression of IQGAP3 seems to be associated with the pathogenesis of breast cancer and suppression of it can inhibit cancer cell growth and metastasis, IQGAP3 may be a potential therapeutic target in human breast cancer.

Sparc/osteonectin, cwcv, and kazal-like domains proteoglycan (testican) 1 (SPOCK1), known as testican-1, were found to be involved in the development and progression of tumors. However, in colorectal cancer (CRC), the expression pattern of SPOCK1 and its functional role remain poorly investigated. In the present study, we explored the role of SPOCK1 in CRC. Our results demonstrated that SPOCK1 is overexpressed in CRC cell lines. SPOCK1 silencing significantly inhibited the proliferation in vitro and the tumor growth in vivo. Furthermore, SPOCK1 silencing significantly attenuated the migration/invasion by reversing the EMT process in CRC cells. Finally, knockdown of SPOCK1 obviously decreased the protein expression levels of p-PI3K and p-Akt in HCT116 cells. In total, our study demonstrated for the first time that knockdown of SPOCK1 inhibits the proliferation and invasion in CRC cells, possibly through the PI3K/Akt signaling pathway. Therefore, SPOCK1 may be a potential therapeutic target for the treatment of CRC.

Ovarian cancer is a malignancy with high mortality among women. Multiple reports show that microRNAs (miRs) act as regulators in ovarian cancer inhibition, while the role of miR-1284 in ovarian cancer is still unknown. This study aimed to investigate the effects of miR-1284 on ovarian cancer cells. Human ovarian cancer cell line OVCAR3 was cultured and transfected with miR-1284 mimics, inhibitors, or control. Viability and apoptosis of transfected cells were then determined by MTT assay, BrdU assay, and flow cytometry. Expression changes of p27, p21, and PI3K/Akt pathway-related proteins were measured by Western blot. Results showed that miR-1284 overexpression suppressed cell viability while increasing the apoptosis in OVCAR3 cells. Moreover, the expression level of p27 was upregulated by miR-1284 overexpression. Furthermore, miR-1284 overexpression and Akt inhibitor GSK690693 downregulated the levels of p-Akt and Bcl-2 while upregulating the levels of Bax and caspase 3. However, miR-1284 suppression attenuated the regulatory effects of GSK690693 on these proteins. In conclusion, miR-1284 could inhibit cell viability via regulating the expression of p27 and induce apoptosis via regulating the PI3K/Akt pathway in OVCAR3 cells.

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin's lymphoma in the adult population, and treatment of DLBCL is still unfavorable. Therefore, there is an urgent requirement to investigate the molecular mechanisms underlying DLBCL tumorigenesis. To study the potential function of microRNA-155 (miR-155) involved in the regulation of lymphoma, we monitored lymphoma cell behavior including proliferation, cell cycle, and apoptosis using CCK-8 and flow cytometry analysis. Real-time PCR was used to detect the expression levels of miR-155 in 118 lymphoma patients' tissues, and Western blot was also used to analyze the expression level of proteins correlated with cell cycle and apoptosis in lymphoma cells. miR-155 expression levels were higher in lymphoma tissues compared with adjacent tissues. Downregulation of miR-155 inhibited lymphoma cell progress by arresting cell cycle in the G0/G1 phase and promoting apoptosis. Cell cycle-correlated proteins (cyclin B1, cyclin D1, and CDK4) were inhibited by downregulation of miR-155. Apoptosis-correlated proteins level (Bax/Bcl-2 and caspase 3 activity) were increased by downregulation of miR-155. In addition, a significant inverse correlation between the level of miR-155 and transforming growth factor-β receptor 2 (TGFBR2) was observed, which has been demonstrated to be a novel tumor suppressor gene. A further in vivo tumor formation study in nude mice indicated that downregulation of miR-155 in lymphoma cells delayed the progress of tumor formation. These findings indicate that miR-155 may serve as a useful potential target for the treatment of lymphoma.

THIS ARTICLE WAS WITHDRAWN BY THE PUBLISHER IN NOVEMBER 2020

This study was designed to investigate the role of miR-183 in modulating cell growth and apoptosis of tongue squamous cell carcinoma SCC25 cell line. Human squamous epithelial cell and squamous cell carcinoma cell line SCC25 was used, and miR-183 was inhibited. Cell growth, colony formation, and apoptotic rate, as well as the expression of caspase 3 and BCL-xL, were detected. Results showed that miR-183 was significantly overexpressed in the SCC25 cell line when compared with normal control. The miR-183 inhibitor reduced cell growth and colony formation, while the apoptosis percentage was significantly increased. The expression of activated caspase 3 and BCL-xL was obviously up- and downregulated in siRNA-transfected cells, respectively. In conclusion, miR-183 contributed to cell growth and proliferation, and suppressed cell apoptosis in SCC25 cells. Therefore, miR-183 might serve as a therapeutic target in tongue squamous cell carcinoma (TSCC).

MicroRNAs (miRNAs) have been shown to be involved in bladder cancer progression. miR-489 (also known as miR-489-3p) was recently reported to be a tumor suppressor in several cancers. However, its exact role and mechanism in the progression of bladder cancer are largely unknown. In this study, we explore the role of miR-489 in the proliferation and invasion of human bladder cancer cells. The miR-489 expression levels were detected in bladder cancer and normal adjacent tissues, as well as in human normal bladder epithelial cells and bladder cancer cell lines. The results showed that miR-489 was sharply reduced in bladder cancer tissues and cell lines. Then the miR-489 mimic or oligo anta-miR-489 was transfected into T24 and UMUC3 bladder cancer cell lines. The results showed that the miR-489 mimic greatly increased the miR-489 level and significantly decreased the proliferation and invasion of T24 and UMUC3 cells. In contrast, the anta-miR-489 had a completely opposite effect on miR-489 expression, cell proliferation, and cell invasion. Moreover, bioinformatics and luciferase reporter gene assays confirmed that miR-489 targeted the mRNA 3'-untranslated region (3'-UTR) region of Jagged1 (JAG1), a Notch ligand. In conclusion, miR-489 suppressed proliferation and invasion of human bladder cancer cells.