Loss of RASSF1A Expression in Colorectal Cancer and Its Association with K-ras Status

Abstract

Background. The RAS-association domain family 1 A (RASSF1A) is a classical member of RAS effectors regulating cell proliferation and apoptosis. Loss of RASSF1A expression may shift the balance towards a growth-promoting effect without the necessity of activating K-ras mutations. Its potential association with K-ras mutations in colorectal cancer (CRC) is unclear. Methods. RASSF1A expression was examined in normal mucosa, adenoma, and tumor tissues of colon and rectum, respectively. We examined the association of RASSF1A expression, mutations of K-ras, and EGFR status in 76 primary CRCs. The relationship between clinicopathological characteristics and RASSF1A expression was also analyzed. Results. RASSF1A expression level decreased progressively in normal mucosa, adenoma and, tumor tissues, and the loss of RASSF1A expression occurred more frequently in tumor tissues. Of 76 primary CRCs, loss of RASSF1A expression and/or K-ras mutations were detected in 77% cases. Loss of RASSF1A expression was more frequent in K-ras wild-type than in mutation cases (63% versus 32%, P = 0.011). Conclusions. Our study indicates that loss of RASSF1A may be involved in pathogenesis of CRC, its expression was found predominantly in K-ras wild-type CRCs, suggesting that it may be another way of affecting RAS signaling, in addition to K-ras mutations.

The Hippo pathway in colorectal cancer

“…Phosphorylation β loss of function in prostate cancer [119], CCL: overexpression inhibits cell proliferation and promote apoptosis in HepG2 cells [87] Mouse double KO: cholangiocarcinoma [46,101], HCC [120] Decreased mRNA level in tumour associated with node metastasis [121], mouse double KO: crypt dysplasia, colon adenoma [46,78,120] RASSF1, RASSF1A TSG: promoter hypermethylation and decrease expression in cancer: thyroid [122], oesophageal [123], prostate [124], colorectal, breast [125] TSG; promoter hypermethylation and decrease expression in CRC [126,127] SAV1, Salvador TSG: LOH and downregulation in renal cell carcinoma [128], no gene mutation in stomach, liver and lung cancer [129] CCL: overexpression induces apoptosis in MCF-7 cells [130] No gene mutation in CRC [129] LATS1 TSG: decrease expression in cancer: glioma [131], NSLC [132], sarcoma [133] and astrocytoma [134]. CCL: LATS1 degradation inhibits apoptosis in MCF10A cells [135] TSG: promoter hypermethylation and mRNA decrease in CRC [86] LATS2 TSG: decrease expression in: malignant mesothelioma (and LOH) [136], NSLC (no mutation found) [137] and astrocytoma [134] OG: overexpression in AML [138], nosopharyngeal carcinoma [139] TSG: downregulation in CRC [87] …”

Ras association domain family 1 isoform A suppresses colonic tumor cell growth through p21WAF1 activation in a p53‐dependent manner

“…Hypermethylation of RASSF1A was also frequently found in early flat type colorectal tumors, characterized by high‐grade dysplasia from early small flat mucosal lesion and exhibited more aggressive behavior. More recently, RASSF1A methylation has also been reported to occur in advanced cancer and associate with distant metastasis . It indicates that RASSF1A methylation may involve in tumor metastasis and invasion of CRC.…”

“…This absence of RASSF1A expression was more frequently observed in the presence of wild‐type KRAS. These results suggested that the inactivation of RASSF1A is a complementary mechanism during the onset of CRC in addition to K‐Ras mutation . Although the exact mechanism of RASSF1A functioning as an RAS effector is not clear, the mutually exclusive relationship between RASSF1A and KRAS mutation specifies that RASSF1A can serve as a therapeutic predictive factor.…”

“…More recently, RASSF1A methylation has also been reported to occur in advanced cancer and associate with distant metastasis. [38][39][40] It indicates that RASSF1A methylation may involve in tumor metastasis and invasion of CRC. Therefore, RASSF1A could be a potential biomarker that would help distinguishing between indolent and aggressive cancers, leading to improvement of cancer screening.…”

Coordinate regulation of the WNT and Hippo pathways by the novel Ras effector NORE1A.

“…The interaction of Ras with RASSF1A promotes the activation of the MST kinases and therefore Hippo pathway activation, leading to down-regulation of YAP. Many tumors exhibit loss of RASSF1A expression [126,261], thus uncoupling Ras from Hippo and facilitating transformation. NORE1A, like RASSF1A, is a RASSF family member that serves as a direct, proapoptotic Ras effector [10,11].…”