Frequent epigenetic inactivation of Wnt inhibitory factor-1 in human gastrointestinal cancers

Taniguchi, Hiroaki; Yamamoto, Hiroyuki; Hirata, Tamaki; Miyamoto, Nobuki; Oki, Masayuki; Nosho, Katsuhiko; Adachi, Yasushi; Endo, Takao; Imai, Kohzoh; Shinomura, Yasuhisa

doi:10.1038/sj.onc.1208910

Cited by 170 publications

(153 citation statements)

References 20 publications

(35 reference statements)

Supporting

Mentioning

142

Contrasting

Order By: Relevance

“…WIF1 is a secreted Wnt antagonist that is often downregulated because of genomic rearrangement, genomic loss or promoter hypermethylation in several human tumors, including colon, lung, breast, prostate, bladder, kidney and salivary gland (Wissmann et al, 2003;Byun et al, 2005;Taniguchi et al, 2005;Ai et al, 2006;Urakami et al, 2006;Queimado et al, 2008;Kawakami et al, 2009). Our study demonstrates that WIF1 downregulation is an early and widespread event in human cervical oncogenesis, which occurs frequently due to promoter hypermethylation.…”

Section: Discussionmentioning

confidence: 64%

Wnt inhibitory factor 1 induces apoptosis and inhibits cervical cancer growth, invasion and angiogenesis in vivo

et al. 2011

View full text Add to dashboard Cite

Aberrant activation of Wingless-type (Wnt)/b-catenin signaling is widespread in human cervical cancer. However, the underlying mechanisms of Wnt activation and the therapeutic potential of Wnt inhibition remain largely unknown. Here, we demonstrate that the Wnt inhibitory factor 1 (WIF1), a secreted Wnt antagonist, is downregulated in all human primary cervical tumors and cell lines analyzed. Our data reveal that WIF1 downregulation occurs due to promoter hypermethylation and is an early event in cervical oncogenesis. WIF1 re-expression upon 5-aza-2 0 -deoxycytidine treatment or WIF1 gene transfer induces significant apoptosis and G 2 /M arrest, and inhibits cervical cancer cell proliferation in vitro. Consistent with this, treatment of established mice tumor xenografts with peritumoral WIF1 gene transfer results in a significant inhibition of cancer growth and invasion. WIF1 treatment causes a significant decrease in intracellular WNT1 and TCF-4 proteins revealing novel Wnt-regulatory mechanisms. Thus, WIF1 causes a major cellular re-distribution of b-catenin and a significant inhibition of the Wnt/b-catenin pathway in tumor cells, as documented by a remarkable reversion in the expression of Wnt/b-catenin transcriptional target genes (E-cadherin, c-Myc, cyclin D1, CD44 and VEGF). Consequently, multiple critical events in tumor progression and metastasis such as cell proliferation, angiogenesis and invasion were inhibited by WIF1. In addition, WIF1 modulated the expression of specific anti-apoptotic and apoptotic proteins, thereby inducing significant apoptosis in vivo. Our findings demonstrate for the first time that WIF1 downregulation by epigenetic gene silencing is an important mechanism of Wnt activation in cervical oncogenesis. Of major clinical relevance, we show that peritumoral WIF1 gene transfer reduces not only cancer growth but also invasion in well-established tumors. Therefore, our data provide novel mechanistic insights into the role of WIF1 in cervical cancer progression, and the important preclinical validation of WIF1 as a potent drug target in cervical cancer treatment.

show abstract

Section: Discussionmentioning

confidence: 64%

Wnt inhibitory factor 1 induces apoptosis and inhibits cervical cancer growth, invasion and angiogenesis in vivo

et al. 2011

View full text Add to dashboard Cite

show abstract

“…35,36 In a recent study, WIF1 was found to be silenced epigenetically in a limited number of Japanese ESCC cell lines and primary tumors. 15 We have systematically analyzed a larger series of ESCC cell lines and a much larger number of primary tumors from Hong Kong Chinese as well as paired normal esophageal tissues, NEE tissues and normal cell lines. The results from these two ethnic groups were similar.…”

Section: Discussionmentioning

confidence: 99%

“…WIF1 was found to be downregulated by methylation in various human malignancies including carcinoma of lungs, mesothelioma, colorectal, various urological and gastrointestinal malignancies. [14][15][16] We also reported that WIF1 is frequently inactivated by methylation in breast cancer. 17 Compared with the low incidence in other parts of the world, nasopharyngeal carcinoma (NPC) and esophageal squamous cell carcinoma (ESCC) are both prevalent malignancies in Southern Asia including Southern China such as Hong Kong, with annual incidence reaching B30 and B100/ 100 000, respectively.…”

mentioning

confidence: 99%

The tumor suppressor Wnt inhibitory factor 1 is frequently methylated in nasopharyngeal and esophageal carcinomas

Chan

Cui

Hasselt

et al. 2007

Laboratory Investigation

View full text Add to dashboard Cite

Aberrant activation of the wingless-type-(Wnt)-signaling pathway is common in many cancers including nasopharyngeal (NPC) and esophageal squamous cell (ESCC) carcinomas, both prevalent in Southern China and Southeast Asia. However, the molecular mechanism leading to this abnormality is still obscure. Wnt inhibitory factor-1 (WIF1) is a secreted antagonist of the Wnt pathway, and is recently shown to be inactivated by epigenetic mechanism in some tumors. Here, we examined whether WIF1 is also inactivated epigenetically in NPC and ESCC. With semiquantitative reverse transcription-PCR and methylation-specific PCR, we detected WIF1 downregulation or silencing in 6/6 of NPC and 12/19 of ESCC cell lines, which is well correlated with its methylation status. Methylation was further confirmed by high-resolution bisulfite genomic sequencing. Methylation was also frequently observed in a large collection of primary tumors of NPC (85%, 55/ 65) and ESCC (27%, 25/92), with WIF1 expressed and unmethylated in normal NPC and esophageal cell lines and normal tissues. Treatment of 5-aza-2 0 -deoxycytidine demethylated WIF1 and induced its expression in NPC and ESCC cell lines, highlighting a direct role of epigenetic inactivation. Ectopic expression of WIF1 in NPC and ESCC tumor cells resulted in significant inhibition of tumor cell colony formation, similar to TP53, and also significant downregulation of b-catenin protein level in NPC cells. Thus, WIF1 functions as a tumor suppressor for both NPC and ESCC through suppressing the Wnt-signaling pathway, but is frequently silenced by epigenetic mechanism in a tumor-specific way. Our study indicates that epigenetic inactivation of WIF1 contributes to the aberrant activation of Wnt pathway and is involved in the pathogenesis of both tumors. WIF1 methylation could also serve as a specific biomarker for these tumors.

show abstract

“…To perform semiquantitative RT-PCR, the ranges of linear amplification for the CASR gene and for the GAPDH gene were studied by using standard curves. 26 Thus, the optimal number of PCR cycles was determined. After PCR, the PCR products were electrophoresed in 2% agarose gels.…”

Section: Semiquantitative Rt-pcr and Real-time Rt-pcrmentioning

confidence: 99%

Epigenetic inactivation of calcium-sensing receptor in colorectal carcinogenesis

et al. 2011

Self Cite

View full text Add to dashboard Cite

Ca 2 þ is a chemopreventive agent for colon cancer. Ion transport systems are often altered in human cancer. The aim of this study was to clarify the alterations of calcium-sensing receptor (CASR), a member of the G proteincoupled receptor family, in colorectal carcinogenesis. We analyzed the expression of CASR in colorectal cancer cell lines and in cancer and adenoma tissues by RT-PCR and immunostaining. In addition, we analyzed methylation of the CASR promoter by using bisulfite sequence analysis and methylation-specific PCR. CASR mRNA and protein expression was significantly downregulated in most of the cancer cell lines. CpG islands were densely methylated in cancer cell lines with reduced CASR mRNA expression. Treatment with a demethylating agent, 5-aza-2 0 -deoxycytidine, and/or a histone deacetylase inhibitor, trichostatin A, restored CASR expression in the cancer cell lines. Disruption of CASR expression in CASR-unmethylated HCT-8 cells blocked the enhancing effect of Ca 2 þ on the cytotoxic response to 5-fluorouracil. CASR expression was observed in normal colonic epithelial cells and was retained in most adenoma tissues. CASR mRNA and protein expression was significantly downregulated in cancer tissues. There was an inverse relationship between CASR expression and degree of differentiation. Immunohistochemical CASR staining was reduced more predominantly in less-differentiated cancer tissues and/or in cancer cells at the invasive front, where nuclear/ cytoplasmic b-catenin was often localized. CASR methylation was detected in 69% of colorectal cancer tissues and 90% of lymph node metastatic tissues and was significantly correlated with reduced CASR expression. CASR methylation was also detected in 32% of advanced adenoma tissues but was detected in only 9% of adenoma tissues and was not detected in hyperplastic polyp tissues. CASR methylation seems to occur at an early stage and progress in colorectal carcinogenesis. The results suggest that epigenetic inactivation of CASR has an important role in colorectal carcinogenesis.

show abstract

Frequent epigenetic inactivation of Wnt inhibitory factor-1 in human gastrointestinal cancers

Cited by 170 publications

References 20 publications

Wnt inhibitory factor 1 induces apoptosis and inhibits cervical cancer growth, invasion and angiogenesis in vivo

Wnt inhibitory factor 1 induces apoptosis and inhibits cervical cancer growth, invasion and angiogenesis in vivo

The tumor suppressor Wnt inhibitory factor 1 is frequently methylated in nasopharyngeal and esophageal carcinomas

Epigenetic inactivation of calcium-sensing receptor in colorectal carcinogenesis

Contact Info

Product

Resources

About