Decreased Expression of the RAS-GTPase Activating Protein RASAL1 Is Associated With Colorectal Tumor Progression

Ohta, Miki; Seto, Motoko; Ijichi, Hideaki; Miyabayashi, Koji; Kudo, Yotaro; Mohri, Dai; Asaoka, Yoshinari; Tada, Motohisa; Tanaka, Yasuo; Ikenoue, Tsuneo; Kanai, Fumihiko; Kawabe, Takao; Omata, Masao

doi:10.1053/j.gastro.2008.09.063

Cited by 82 publications

(88 citation statements)

References 32 publications

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“…32 Until recently, a role for RasGAPs in colorectal cancers (CRC) was unknown, but recent studies identified RASAL as being significantly downregulated in all CRC lines that express wild-type K-Ras. 34 Knockdown and overexpression experiments support a role of RASAL as a negative regulator of wild-type K-Ras in CRC cells. Primary CRC tumors revealed a correlation between RASAL levels and CRC disease progression, implicating a prognostic role for RASAL in colon cancer.…”

Section: Differential Expression Of Gaps In Cancermentioning

confidence: 90%

“…Primary CRC tumors revealed a correlation between RASAL levels and CRC disease progression, implicating a prognostic role for RASAL in colon cancer. 34 Interestingly, reduced RASAL levels were predominantly observed in tumors of the distal colon and rectum, indicating that particular cells defined by their tissue location are particularly vulnerable to RASAL depletion. Similar to the studies described above, methylation of the RASAL gene in several CRC lines was observed, which further emphasizes epigenetic silencing of RASAL contributing to tumorigenesis.…”

Section: Differential Expression Of Gaps In Cancermentioning

confidence: 99%

“…32 Recently, loss of RASAL activity was correlated with hyperactive Ras in the colon and hepatocellular carcinoma lacking oncogenic Ras. 33,34 In some cancers, diminution of RASAL is probably due to the downregulation of the transcription factor PITX1, which is required for RASAL mRNA expression. 35 Furthermore, expression of DAB2IP, a less well-characterized member of the Syn-GAP family, is often silenced in hepatocellular carcinoma.…”

Section: Functional Differences Of Ras Isoforms and Differential Gap mentioning

confidence: 99%

“…Similar to the studies described above, methylation of the RASAL gene in several CRC lines was observed, which further emphasizes epigenetic silencing of RASAL contributing to tumorigenesis. 34 Aberrant activation of wild-type Ras and its downstream effector pathways is also common in human hepatocellular carcinomas (HCC). In a large collection of human HCC, Calvisi et al identified that in HCC with hyperactive wild-type Ras, but lacking Ras mutations, either RASAL, DAB2IP, NF1, or the RASAL inducer PTX1 was downregulated.…”

Section: Differential Expression Of Gaps In Cancermentioning

confidence: 99%

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Differential Regulation of RasGAPs in Cancer

et al. 2011

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Ever since their discovery as cellular counterparts of viral oncogenes more than 25 years ago, much progress has been made in understanding the complex networks of signal transduction pathways activated by oncogenic Ras mutations in human cancers. The activity of Ras is regulated by nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs), and much emphasis has been put into the biochemical and structural analysis of the Ras/GAP complex. The mechanisms by which GAPs catalyze Ras-GTP hydrolysis have been clarified and revealed that oncogenic Ras mutations confer resistance to GAPs and remain constitutively active. However, it is yet unclear how cells coordinate the large and divergent GAP protein family to promote Ras inactivation and ensure a certain biological response. Different domain arrangements in GAPs to create differential protein-protein and protein-lipid interactions are probably key factors determining the inactivation of the 3 Ras isoforms H-, K-, and N-Ras and their effector pathways. In recent years, in vitro as well as cell-and animal-based studies examining GAP activity, localization, interaction partners, and expression profiles have provided further insights into Ras inactivation and revealed characteristics of several GAPs to exert specific and distinct functions. This review aims to summarize knowledge on the cell biology of RasGAP proteins that potentially contributes to differential regulation of spatiotemporal Ras signaling.

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Section: Differential Expression Of Gaps In Cancermentioning

confidence: 90%

Section: Differential Expression Of Gaps In Cancermentioning

confidence: 99%

Section: Functional Differences Of Ras Isoforms and Differential Gap mentioning

confidence: 99%

Section: Differential Expression Of Gaps In Cancermentioning

confidence: 99%

See 2 more Smart Citations

Differential Regulation of RasGAPs in Cancer

et al. 2011

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“…Among the co-expressed genes, RASAL1 was also located on chromosome 12, relatively close to CR613944. This gene has been reported to contribute to colon tumor progression and gastric tumorigenesis (Ohta et al, 2009;Seto et al, 2011). Two lincRNAs, CR613944 and AX747582, were downregulated in H2 and co-expressed with WISP2 mRNA, which is translated into an important regulator involved in tumor cell invasion and metastasis (Fritah et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Long Non-coding RNAs are Differentially Expressed in Hepatocellular Carcinoma Cell Lines with Differing Metastatic Potential

Fang

Sun²,

Chen³

et al. 2015

Asian Pacific Journal of Cancer Prevention

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(Talmadge and Fidler, 2010). A salient feature of metastasis is the ability of cancer cells to colonize specific organ sites (Hanahan and Weinberg, 2011). For instance, HCC cells metastasize to the lung more frequently than the lymph nodes. It is well recognized that the probability of metastatic seeding and growth is determined by both intrinsic genetic properties of the cancer cells involved and characteristics of the stromal microenvironment that surrounds them (Lu and Kang, 2007;Nguyen et al., 2009). Functional genomic analysis of HCC cell lines with different organ-specific metastatic potential may provide new opportunities for identifying diagnostic biomarkers and developing therapies to combat HCC metastasis.Large-scale genomic studies have demonstrated that the mammalian genome encodes many thousands Ting-Ting Fang et al

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The genetic duet of concurrent RASAL1 and PTEN alterations promotes cancer aggressiveness by cooperatively activating the PI3K–AKT pathway

Shen,

Tan,

Liu

et al. 2024

Molecular Oncology

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The significance of the prominent tumor suppressor gene for RAS protein activator‐like 1 (RASAL1) could be better understood by combined genetic, clinical, and functional studies. Here, we investigated the oncogenic and clinical impacts of genetic alterations of RASAL1, particularly when coexisting with genetic alterations of the gene for phosphatase and tensin homolog (PTEN), in 9924 cancers of 33 types in the TCGA database. We found common concurrent genetic alterations of the two genes, which were cooperatively associated with activation of the phosphatidylinositol 3‐kinase (PI3K)–AKT pathway, with cancer progression and mortality rates being 46.36% and 31.72% with concurrent gene alterations, versus 29.80% and 16.93% with neither gene alteration (HR 1.64, 95% CI 1.46–1.84 and 1.77, 95% CI 1.53–2.05), respectively. This was enhanced by additional tumor protein p53 (TP53) gene alterations, with cancer progression and mortality rates being 47.65% and 34.46% with coexisting RASAL1, PTEN, and TP53 alterations versus 25.30% and 13.11% with no alteration (HR 2.21, 95% CI 1.92–2.56 and 2.76, 95% CI 2.31–3.30), respectively. In the case of breast cancer, this genetic trio was associated with a triple‐negative risk of 68.75% versus 3.83% with no genetic alteration (RR 17.94, 95% CI 9.60–33.51), consistent with the aggressive nature of triple‐negative breast cancer. Mice with double knockouts of Rasal1 and Pten displayed robust Pi3k pathway activation, with the development of metastasizing malignancies, while single gene knockout resulted in only benign neoplasma. These results suggest that RASAL1, like PTEN, is a critical player in negatively regulating the PI3K–AKT pathway; defect in RASAL1 causes RAS activation, thus initiating the PI3K–AKT pathway signaling, which cannot terminate with concurrent PTEN defects. Thus, the unique concurrent RASAL1 and PTEN defects drive oncogenesis and cancer aggressiveness by cooperatively activating the PI3K–AKT pathway. This represents a robust genetic mechanism to promote human cancer.

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Decreased Expression of the RAS-GTPase Activating Protein RASAL1 Is Associated With Colorectal Tumor Progression

Cited by 82 publications

References 32 publications

Differential Regulation of RasGAPs in Cancer

Differential Regulation of RasGAPs in Cancer

Long Non-coding RNAs are Differentially Expressed in Hepatocellular Carcinoma Cell Lines with Differing Metastatic Potential

The genetic duet of concurrent RASAL1 and PTEN alterations promotes cancer aggressiveness by cooperatively activating the PI3K–AKT pathway

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