Yes-Associated Protein 1 Exhibits Oncogenic Property in Gastric Cancer and Its Nuclear Accumulation Associates with Poor Prognosis

Kang, Wei; Tong, Joanna H.M.; Chan, Anthony W.H.; Lee, Tin‐Lap; Lung, Raymond Wai Ming; Leung, Patrick P.S.; So, Ken K.Y.; Wu, Kaijie; Fan, Daiming; Yu, Jun; Sung, Joseph J.Y.; To, Ka‐Fai

doi:10.1158/1078-0432.ccr-10-2467

Cited by 229 publications

(232 citation statements)

References 29 publications

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“…Another interesting biochemical observation was the activation of ERK in our Mob1-deficient keratinocytes: no connection between MOB1 and ERK has been reported to date. With respect to Hippo signaling, ERK can be activated by YAP1 (49) or suppressed by NF2 (50) or MST2 (51). Since NF2 and phospho-MST1/2 were not decreased in our Mob1-deficient keratinocytes (data not shown), we speculate that the increased YAP1 in these cells may have triggered their abnormal ERK activation.…”

Section: Discussionmentioning

confidence: 84%

Cancer susceptibility and embryonic lethality in Mob1a/1b double-mutant mice

et al. 2012

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Mps one binder 1a (MOB1A) and MOB1B are key components of the Hippo signaling pathway and are mutated or inactivated in many human cancers. Here we show that intact Mob1a or Mob1b is essential for murine embryogenesis and that loss of the remaining WT Mob1 allele in Mob1a Δ/Δ 1b tr/+ or Mob1a Δ/+ 1b tr/tr mice results in tumor development. Because most of these cancers resembled trichilemmal carcinomas, we generated doublemutant mice bearing tamoxifen-inducible, keratinocyte-specific homozygous-null mutations of Mob1a and Mob1b (kDKO mice). kDKO mice showed hyperplastic keratinocyte progenitors and defective keratinocyte terminal differentiation and soon died of malnutrition. kDKO keratinocytes exhibited hyperproliferation, apoptotic resistance, impaired contact inhibition, enhanced progenitor self renewal, and increased centrosomes. Examination of Hippo pathway signaling in kDKO keratinocytes revealed that loss of Mob1a/b altered the activities of the downstream Hippo mediators LATS and YAP1. Similarly, YAP1 was activated in some human trichilemmal carcinomas, and some of these also exhibited MOB1A/1B inactivation. Our results clearly demonstrate that MOB1A and MOB1B have overlapping functions in skin homeostasis, and exert their roles as tumor suppressors by regulating downstream elements of the Hippo pathway.

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Section: Discussionmentioning

confidence: 84%

Cancer susceptibility and embryonic lethality in Mob1a/1b double-mutant mice

et al. 2012

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“…Hence, the apoptotic response to siRRM2 appeared to be cell context-dependent. It is uncertain whether the different TP53 status might contribute to the different apoptotic responses as MKN1 and MKN28 cells harbor the TP53 mutation, whereas AGS cells carry the wild type TP53 (17). It has been reported that antisense RRM2 downregulated RRM2 expression and sensitized a prostate cancer cell line PC3 to UV radiation (27).…”

Section: Discussionmentioning

confidence: 99%

“…Western blot analysis was performed as previously described (17). RRM2 protein was detected with a polyclonal anti-RRM2 antibody (Santa Cruz, 10846, 1:500).…”

Section: Cell Lines and Clinical Gastric Adenocarcinoma Samplesmentioning

confidence: 99%

“…Cell proliferation was assessed using CellTiter 96 ® Non-Radioactive Cell Proliferation Assay (MTT; Promega, Madison, WI, USA) according to the manufacturer's instructions. Monolayer colony formation assay was performed as described in our previous report (17). Ten days after transfection of siRRM2 or scramble siRNA, the colonies were fixed and stained with 2% crystal violet.…”

Section: Cell Lines and Clinical Gastric Adenocarcinoma Samplesmentioning

confidence: 99%

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Targeting ribonucleotide reductase M2 subunit by small interfering RNA exerts anti-oncogenic effects in gastric adenocarcinoma

et al. 2014

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Abstract. Ribonucleotide reductase M2 subunit (RRM2) is one of the two subunits of human ribonucleotide reductase which plays a critical role in tumor progression. The aim of the present study was to analyze its expression, clinical significance and biological functions in gastric adenocarcinoma. We observed the upregulation of RRM2 mRNA and protein in all nine gastric cancer cell lines examined. In paired primary gastric cancers, both mRNA and protein levels of RRM2 were significantly upregulated in tumors compared with the corresponding non-tumorous gastric tissues. RRM2 protein expression correlated with higher tumor grade, advanced T stage and poor disease-specific survival. RRM2 knockdown in gastric cancer cell lines AGS, MKN1 and MKN28 significantly suppressed cell proliferation, inhibited monolayer colony formation, reduced cell invasion and induced apoptosis. Downregulation of RRM2 suppressed xenograft formation in vivo. Collectively, these findings suggest that RRM2 plays a crucial role in gastric tumorigenesis and may serve as a potential prognostic marker and therapeutic target in gastric cancer.

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“…The MAPK pathway is known to be activated in a broad spectrum of human tumors, including human colorectal (25) and gastric cancer (26) and melanoma (27). We observed that activation of the MEK/ERK pathway was relatively weak in breast cancer cells, yet TM induced constitutive activation of the pathway as evidenced by increased phosphorylation (activation) form of ERK1/2 (P-ERK1/2).…”

Section: Discussionmentioning

confidence: 98%

Inhibition of mitogen-activated protein kinase signaling pathway sensitizes breast cancer cells to endoplasmic reticulum stress-induced apoptosis

et al. 2016

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Abstract. Accumulation of unfolded proteins in the endoplasmic reticulum (ER) induces ER stress which is observed in many human diseases, including breast cancer. Cellular adaptation to ER stress is mediated by the unfolded protein response (UPR), which aims at restoring ER homeostasis. Higher levels of GRP78 expression indicates constitutive activation of the UPR in breast cancer leading to breast cancer cells that are relatively resistant to ER stress-induced apoptosis. Tunicamycin (TM), an ER stress inducer, constitutively activates the mitogen-activated protein kinase (MAPK)/extracellular signal regulated kinase (ERK), and (MEK)/ERK pathway which plays a role in upregulation of GRP78 by ER stress in that inhibition of MEK by U0126 reduces the levels of GRP78 and blocks its upregulation by TM. Inhibition of the MEK/ERK pathway by U0126 sensitizes breast cancer cells to TM-induced apoptosis. Inhibition of GRP78 by siRNA knockdown enhances TM-and U0126-induced apoptosis in breast cancer cells. This sensitization of breast cancer cells to TM-induced apoptosis by inhibition of MEK/ERK and GRP78 is caspase-dependent, at least in part, by activation of caspase-4. These results seem to indicate that GRP78 has potential as a chemotherapeutical target and have important implications for new treatment strategies in breast cancer by combination with agents that induce ER stress with inhibitors of the MEK/ERK pathway.

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Yes-Associated Protein 1 Exhibits Oncogenic Property in Gastric Cancer and Its Nuclear Accumulation Associates with Poor Prognosis

Cited by 229 publications

References 29 publications

Cancer susceptibility and embryonic lethality in Mob1a/1b double-mutant mice

Cancer susceptibility and embryonic lethality in Mob1a/1b double-mutant mice

Targeting ribonucleotide reductase M2 subunit by small interfering RNA exerts anti-oncogenic effects in gastric adenocarcinoma

Inhibition of mitogen-activated protein kinase signaling pathway sensitizes breast cancer cells to endoplasmic reticulum stress-induced apoptosis

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