PP2A fulfills its promises as tumor suppressor: which subunits are important?

Reversible phosphorylation of proteins, catalyzed by kinases and phosphatases, is a key regulatory mechanism in the control of multiple cellular signal transduction pathways. Uncontrolled regulation by the altered phosphorylation state of the components of these pathways often leads to increased cell proliferation and cell transformation. Many viruses encode oncogenic proteins, required for their efficient viral replication, which deregulate the activity of host cell proteins. This might program cells to a malignant state, underlying the molecular mechanism of tumor formation and cancer development. Recent studies reveal a role for a specific form of protein phosphatase 2A (PP2A) in viral-induced cell transformation by interaction with the small t antigen (ST) of the DNA tumor simian virus 40 (SV40).     

Dickkopf1: A tumor suppressor or metastasis promoter?

Dickkopf1 (DKK1), a secreted inhibitor of the Wnt/β‐catenin pathway, is a negative regulator of bone formation. DKK1 acts as a switch that transitions prostate cancer bone metastases from osteolytic to osteoblastic and also is an active indicator of poor outcome for multiple myeloma. However, in other tumor types, DKK1 upregulation or overexpression suppresses tumor growth. Thus, the role of DKK1 in cancer appears to be diverse. This raises a question: Could the increased levels of DKK1 still be tumor protective when observed in high levels in the serum of patients? Here, we summarize the diverse, seemingly contradicting roles of DKK1 and attempt to explain the apparent dichotomy in its activity. We propose that DKK1 is a critical secreted factor that modulates microenvironment. Based on the location and components of the microenvironment DKK1 will support different outcomes.     

A knotty turnabout?: Akt1 as a metastasis suppressor

Akt is well known to enhance malignancy and is recognized as a key target for antineoplastic therapies. However, intriguing findings reported by Yoeli-Lerner et al. in the November 23, 2005 issue of Molecular Cell, suggest a novel, antimetastasis function of Akt: activation of Akt1 inhibited invasion in some cancer cells. One possible mechanism for this surprising phenotype was that Akt activated the E3 ubiquitin ligase HDM2, causing ubiquitination and degradation of NFAT, an invasion-promoting factor. These findings clearly justify further investigations and, if validated in vivo, call for reevaluation of some Akt-targeting therapeutic strategies currently under development.     

MicroRNA function in cancer: oncogene or a tumor suppressor?

MicroRNAs (miRNAs) are small noncoding, double-stranded RNA molecules that can mediate the expression of target genes with complementary sequences. About 5,300 human genes have been implicated as targets for miRNAs, making them one of the most abundant classes of regulatory genes in humans. MiRNAs recognize their target mRNAs based on sequence complementarity and act on them to cause the inhibition of protein translation by degradation of mRNA. Besides contributing to development and normal function, microRNAs have functions in various human diseases. Given the importance of miRNAs in regulating cellular differentiation and proliferation, it is not surprising that their misregulation is linked to cancer. In cancer, miRNAs function as regulatory molecules, acting as oncogenes or tumor suppressors. Amplification or overexpression of miRNAs can down-regulate tumor suppressors or other genes involved in cell differentiation, thereby contributing to tumor formation by stimulating proliferation, angiogenesis, and invasion; i.e., they act as oncogenes. Similarly, miRNAs can down-regulate different proteins with oncogenic activity; i.e., they act as tumor suppressors. This review will highlight the recent discoveries regarding miRNAs and their importance in cancer.     

Telomerase and telomere stability: a new class of tumor suppressor?

Introduction of telomerase into normal cells provides telomere maintenance and an extended cellular life span, establishing the critical role of telomere attrition in cellular senescence. Additional data surrounding this observation suggest that expression of telomerase renders these "mortal" cells genomically stable with decreased frequencies of mutation, ultimately leading to continued proliferation without signs of changes typically associated with progression to a cancer-like phenotype. Interestingly, oncogenic insult after exogenous telomerase expression does not result in cellular transformation, yet addition of an oncogene first followed by telomerase does transform cells. Taken together, these results imply that order of addition is important for telomerase-mediated genomic protection and that telomerase expression is critical for the transformation process. The hypothesis proposed here is that telomerase, via its function in telomere stabilization, is capable of protecting cells from acquiring the required mutations and genomic instability necessary for malignant transformation, suggesting that telomerase is not an oncogene but may act as a novel class of tumor suppressor.     

miR-33a functions as a tumor suppressor in melanoma by targeting HIF-1α

Background: Our previous findings showed that miR-33 expressed abnormally in clinical specimens of melanoma, but the exact molecular mechanism has not been elucidated. Object: To determine miR-33''s roles in melanoma and confirm whether HIF-1α is a direct target gene of miR-33a. Methods: First miR-33a/b expression levels were detected in HM, WM35, WM451, A375 and SK-MEL-1. Then lentiviral vectors were constructed to intervene miR-33a expression in melanoma cells. Cell proliferation, invasion and metastasis were detected. A375 cells mice model was performed to test the tumorigenesis of melanoma in vivo. Finally the dual reporter gene assay was carried out to confirm whether HIF-1α is a direct target gene of miR-33a. Results: MiR-33a/b exhibited a lower expression in WM35, WM451, A375 and SK-MEL-1 of the metastatic skin melanoma cell lines than that in HM. Then inhibition of miR-33a expression in WM35 and WM451 cell lines could promote cell proliferation, invasion and metastasis. Conversely, increased expression of miR-33a in A375 cells could inhibit cellproliferation, invasion and metastasis. In vivo tests also confirmed that overexpression of miR-33a in A375 cells significantly inhibited melanoma tumorigenesis. Finally, we confirmed that HIF-1α is a direct target gene of miR-33a. Conclusion: The newly identified miR-33a/HIF-1α axis might provide a new strategy for the treatment of melanoma.     

An identity crisis for fps/fes: oncogene or tumor suppressor?

Fps/Fes proteins were among the first members of the protein tyrosine kinase family to be characterized as dominant-acting oncoproteins. Addition of retroviral GAG sequences or other experimentally induced mutations activated the latent transforming potential of Fps/Fes. However, activating mutations in fps/fes had not been found in human tumors until recently, when mutational analysis of a panel of colorectal cancers identified four somatic mutations in sequences encoding the Fps/Fes kinase domain. Here, we report biochemical and theoretical structural analysis demonstrating that three of these mutations result in inactivation, not activation, of Fps/Fes, whereas the fourth mutation compromised in vivo activity. These results did not concur with a classic dominant-acting oncogenic role for fps/fes involving activating somatic mutations but instead raised the possibility that inactivating fps/fes mutations might promote tumor progression in vivo. Consistent with this, we observed that tumor onset in a mouse model of breast epithelial cancer occurred earlier in mice targeted with either null or kinase-inactivating fps/fes mutations. Furthermore, a fps/fes transgene restored normal tumor onset kinetics in targeted fps/fes null mice. These data suggest a novel and unexpected tumor suppressor role for Fps/Fes in epithelial cells.     

DPPIV/CD26: a tumor suppressor or a marker of malignancy?

Dipeptidyl peptidase IV (DPPIV/CD26) is a multifunctional protein with intrinsic peptidase activity that inactivates or degrades some bioactive peptides. It is the main cellular binding protein for ecto-adenosine deaminase and interacts with extracellular matrix proteins, besides participating in different signaling pathways. Due to these multiple functions, DPPIV/CD26 has been shown to be closely related to the tumor process. It has been reported that the progression of certain types of cancer is accompanied by a decrease in DPPIV/CD26 expression, and studies have shown that the malignant phenotype can be reverted when DPPIV/CD26 expression is induced in these cancer cells, characterizing this protein as a tumor suppressor. On the other hand, DPPIV/CD26 was described as a protein associated with invasion and metastatic spread, characterizing it as a marker of malignancy. Thus, this review explores the roles of DPPIV/CD26 expression in tumor progression in different types of cancer and demonstrates the importance of this protein as a promising therapeutic target and tumor biomarker.     

Is miR-29 an oncogene or tumor suppressor in CLL?

B-cell chronic lymphocytic leukemia (CLL), the most common leukemia in the Western world. CLL occurs in two forms, aggressive and indolent. Aggressive CLL is characterized by high ZAP-70 expression and unmutated IgH V(H); indolent CLL shows low ZAP-70 expression and mutated IgH V(H). We recently found that miR-29 is up-regulated in indolent human B-CLL, compared to aggressive B-CLL and normal CD19(+) B-cells. To determine the role of miR-29 in CLL, we generated transgenic mice over-expressing miR-29 in mouse B-cells. Recently we reported that miR-29 transgenic mice develop indolent CLL phenotype. Interestingly, our previous findings suggest that miR-29 targets expression of TCL1, a critical oncogene in aggressive CLL, indicating that miR-29 might function as a tumor suppressor in CLL. Here we discuss these results and provide additional insights into function of miR-29 in CLL.