miRNAs are non-coding RNA sequences of approximately 22 nucleotides that interact with genes by inhibiting their translation through binding to their 3' or 5' UTR regions. Following their discovery, the role they play in the development of various pathologies, particularly cancer, has been studied. In this context, miR-7 is described as an important factor in the development of cancer because of its role as a tumor suppressor, regulating a large number of genes involved in the development and progression of cancer. Recent data support the function of miR-7 as a prognostic biomarker in cancer, and miR-7 has been proposed as a strategy in cancer therapy. In this work, the role of miR-7 in various types of cancer is reviewed, illustrating its regulation, direct targets, and effects, as well as its possible relationship to the clinical outcome of cancer patients.

Members of the Bcl-2 family are proteins that play an essential role in the regulation of apoptosis, a crucial process in development and normal physiology in multicellular organisms. The essential mechanism of this family of proteins is given by the role of pro-survival proteins, which inhibit apoptosis by their direct binding with their counterpart, the effector proteins of apoptosis. This family of proteins was named after the typical member Bcl-2, which was named for its discovery and abnormal expression in B-cell lymphomas. Subsequently, the structure of one of its members BCL-xL was described, which allowed one to understand much of the molecular mechanism of this family. Due to its role of BCL-xL in the regulation of cell survival and proliferation, it has been of great interest in its study. Due to this, it is important to research its role regarding the development and progression of human malignancies, especially in hematologic malignancies. Due to its variation in expression in cancer, it has been suggested that BCL-xL can or cannot play a role in cancer depending on the cellular or tissue context. This review discusses recent advances in its transcriptional regulation of BCL-xL, as well as the advances regarding the activities of BCL-xL in hematological malignancies, its possible role as a biomarker, and its possible clinical relevance in these malignancies.

The interaction between CD40, and its ligand, CD154, is essential for the development of humoral and cellular immune responses. The selective inhibition or activation of this pathway forms the basis for the development of new therapeutics against immunologically based diseases and malignancies. We are developing a gene fusion of Salmonella typhi OmpC protein expressing the CD154 Tyr140-Ser-149 amino acid strand. This OmpC-CD154 binds CD40 and activates B cells. In this study, we demonstrate that OmpC-CD154_p treatment inhibits cell growth, proliferation and induced apoptosis in the B-NHL cell lines Raji and Ramos. The Bcl-2 family proteins were regulated and the Bcl-6 and YY1 oncoproteins were inhibited. p38 MAPK activation is an important mechanism underlying the effect on proliferation and apoptosis mediated by this fusion protein. This study establishes a basis for the possible use of fusion protein OmpC-CD154 as an alternative treatment for B-NHL.

The discovery and description of the role of microRNAs has become very important, specifically due to their participation in the regulation of proteins and transcription factors involved in the development of cancer. microRNA-7 (miR-7) has been described as a negative regulator of several proteins involved in cancer, such as YY1 and KLF4. We have recently reported that YY1 and KLF4 play a role in non-Hodgkin lymphoma (NHL) and that the expression of KLF4 is regulated by YY1. Therefore, in this study we analyzed the role of miR-7 in NHL through the negative regulation of YY1 and KLF4. qRT-PCR showed that there is an inverse expression of miR-7 in relation to the expression of YY1 and KLF4 in B-NHL cell lines. The possible regulation of YY1 and KLF4 by miR-7 was analyzed using the constitutive expression or inhibition of miR-7, as well as using reporter plasmids containing the 3 'UTR region of YY1 or KLF4. The role of miR-7 in NHL, through the negative regulation of YY1 and KLF4 was determined by chemoresistance and migration assays. We corroborated our results in cell lines, in a TMA from NHL patients including DLBCL and follicular lymphoma subtypes, in where we analyzed miR-7 by ISH and YY1 and KLF4 using IHC. All tumors expressing miR-7 showed a negative correlation with YY1 and KLF4 expression. In addition, expression of miR-7 was analyzed using the GEO Database; miR-7 downregulated expression was associated with pour overall-survival. Our results show for the first time that miR-7 is implicate in the cell migration and chemoresistance in NHL, through the negative regulation of YY1 and KLF4. That also support the evidence that YY1 and KLF4 can be a potential therapeutic target in NHL.

Prior work indicates DEPTOR expression in multiple myeloma cells could be a therapeutic target. DEPTOR binds to mTOR via its PDZ domain and inhibits mTOR kinase activity. We previously identified a drug, which prevented mTOR-DEPTOR binding (NSC126405) and induced multiple myeloma cytotoxicity. We now report on a related therapeutic, drug 3g, which induces proteasomal degradation of DEPTOR. DEPTOR degradation followed drug 3g binding to its PDZ domain and was not due to caspase activation or enhanced mTOR phosphorylation of DEPTOR. Drug 3g enhanced mTOR activity, and engaged the IRS-1/PI3K/AKT feedback loop with reduced phosphorylation of AKT on T308. Activation of TORC1, in part, mediated multiple myeloma cytotoxicity. Drug 3g was more effective than NSC126405 in preventing binding of recombinant DEPTOR to mTOR, preventing binding of DEPTOR to mTOR inside multiple myeloma cells, in activating mTOR and inducing apoptosis in multiple myeloma cells. In vivo, drug 3g injected daily abrogated DEPTOR expression in xenograft tumors and induced an antitumor effect although modest weight loss was seen. Every-other-day treatment, however, was equally effective without weight loss. Drug 3g also reduced DEPTOR expression in normal tissues. Although no potential toxicity was identified in hematopoietic or hepatic function, moderate cardiac enlargement and glomerular mesangial hypertrophy was seen. DEPTOR protected multiple myeloma cells against bortezomib suggesting anti-DEPTOR drugs could synergize with proteasome inhibitors (PI). Indeed, combinations of drug NSC126405 + bortezomib were synergistic. In contrast, drug 3g was not and was even antagonistic. This antagonism was probably due to prevention of proteasomal DEPTOR degradation.

The p38 MAPK is constitutively activated in B-NHL cell lines and regulates chemoresistance. Accordingly, we hypothesized that activated p38 MAPK may be associated with the in vivo unresponsiveness to chemotherapy in B-NHL patients.

Tissue microarrays generated from eighty untreated patients with Diffused Large B Cell Lymphoma (DLBCL) were examined by immunohistochemistry for the expression of p38 and phospho p38 (p-p38) MAPK. In addition, both Bcl-2 and NF-κB expressions were determined. Kaplan Meier analysis was assessed.

Tumor tissues expressed p38 MAPK (82 %) and p-p38 MAPK (30 %). Both p38 and p-p38 MAPK expressions correlated with the high score performance status. A significant correlation was found between the expression p-p38 and poor response to CHOP. The five year median follow-up FFS was 81 % for p38(-) and 34 % for p38(+) and for OS was 83 % for p38(-) and 47 % for p38(+). The p-p38(+) tissues expressed Bcl-2 and 90 % of p-p38(-) where Bcl-2(-). The coexpression of p-p38 and Bcl-2 correlated with pool EFS and OS. There was no correlation between the expression of p-p38 and the expression of NF-κB.

The findings revealed, for the first time, that a subset of patients with DLBCL and whose tumors expressed high p-p38 MAPK responded poorly to CHOP therapy and had poor EFS and OS. The expression of p38, p-p38, Bcl2 and the ABC subtype are significant risk factors both p38 and p-p38 expressions remain independent prognostic factors.

Krüppel-Like Factor 4 (KLF4) is a member of the KLF transcription factor family, and evidence suggests that KLF4 is either an oncogene or a tumor suppressor. The regulatory mechanism underlying KLF4 expression in cancer, and specifically in lymphoma, is still not understood. Bioinformatics analysis revealed two YY1 putative binding sites in the KLF4 promoter region (-950 bp and -105 bp). Here, the potential regulation of KLF4 by YY1 in NHL was analyzed. Mutation of the putative YY1 binding sites in a previously reported system containing the KLF4 promoter region and CHIP analysis confirmed that these binding sites are important for KLF4 regulation. B-NHL cell lines showed that both KLF4 and YY1 are co-expressed, and transfection with siRNA-YY1 resulted in significant inhibition of KLF4. The clinical implications of YY1 in the transcriptional regulation of KLF4 were investigated by IHC in a TMA with 43 samples of subtypes DLBCL and FL, and all tumor tissues expressing YY1 demonstrated a correlation with KLF4 expression, which was consistent with bioinformatics analyses in several databases. Our findings demonstrated that KLF4 can be transcriptionally regulated by YY1 in B-NHL, and a correlation between YY1 expression and KLF4 was found in clinical samples. Hence, both YY1 and KLF4 may be possible therapeutic biomarkers of NHL.