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Reduced FBXW7 expression in pancreatic cancer correlates with poor prognosis and chemotherapeutic resistance via accumulation of MCL1.

ABSTRACT: Pancreatic cancer is a highly malignant tumor type with poor outcomes, and elucidation of the mechanisms involved in cancer progression and therapeutic resistance is critical. FBXW7 is a key regulator of tumor malignant potential, and its substrate MCL1 regulates therapeutic resistance in human malignancies. Therefore, determination of the relevance of FBXW7 expression is critical for improving patient outcomes. In this study, we investigated the function and clinical significance of FBXW7 in pancreatic cancer. FBXW7 expression was evaluated by immunohistochemistry in 122 pancreatic cancer tissues. Reduced FBXW7 expression was significantly associated with advanced venous invasion, high MCL1 expression, enhanced Ki-67 expression, and poor prognosis and was an independent poor prognostic factor. Among patients who underwent gemcitabine treatment after surgery, reduced FBXW7 expression was also significantly associated with poor prognosis. Knockdown of FBXW7 in vitro enhanced cell proliferation, and migration, and invasion abilities and promoted gemcitabine and nab-paclitaxel chemoresistance in pancreatic cancer cells. Moreover, FBXW7-knockdown cells showed accumulation of MCL1, and the enhanced chemoresistance observed in FBXW7-knockdown cells was eliminated by MCL1 suppression. These results suggested that FBXW7 was associated with cancer progression and mediated sensitivity to gemcitabine and nab-paclitaxel via MCL1 accumulation in pancreatic cancer. Thus, the FBXW7/MCL1 axis may be a promising therapeutic tool to overcome refractory pancreatic cancer.

SUBMITTER: Ishii N

PROVIDER: S-EPMC5762537 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Reduced FBXW7 expression in pancreatic cancer correlates with poor prognosis and chemotherapeutic resistance via accumulation of MCL1.

Ishii Norihiro N Araki Kenichiro K Yokobori Takehiko T Gantumur Dorgormaa D Yamanaka Takahiro T Altan Bolag B Tsukagoshi Mariko M Igarashi Takamichi T Watanabe Akira A Kubo Norio N Hosouchi Yasuo Y Kuwano Hiroyuki H Shirabe Ken K

Oncotarget 20171106 68

Pancreatic cancer is a highly malignant tumor type with poor outcomes, and elucidation of the mechanisms involved in cancer progression and therapeutic resistance is critical. FBXW7 is a key regulator of tumor malignant potential, and its substrate MCL1 regulates therapeutic resistance in human malignancies. Therefore, determination of the relevance of FBXW7 expression is critical for improving patient outcomes. In this study, we investigated the function and clinical significance of FBXW7 in pa ...[more]

PMID: 29348852

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Project description:IQGAPs is a family of proteins which comprises three members, in humans. The expression pattern and role of IQGAP1 has been well established in many cancers, whereas those of IQGAP2 and IQGAP3, have mostly remained unexplored. We used available large datasets, to explore the pan-cancer status of these two genes in-silico. Here we have analysed their mRNA expression and correlation with survivability in eight different cancers, including lung, breast, gastric, brain, colorectal, prostate, liver and kidney cancers and, their subtypes. The mRNA expression of IQGAP2 and IQGAP3 in individual cancers were analysed in two different publicly available databases viz. Oncomine and TCGA. The prognostic value of these genes in lung, breast and gastric cancer was analysed using Kaplan-Meier Plotter database, whereas for brain, colorectal, liver, prostate and kidney cancers, SurvExpress database was used. These results were validated by immunohistochemistry in cancer tissues (stomach, prostate, brain, colorectal). Moreover, we did IQGAP2 and IQGAP3 genomic alteration and, promoter methylation analysis using cBioportal and Wanderer web tool, respectively. Most of the cancer types (lung, breast, prostate, brain, gastric, liver, kidney and colorectal) showed increased IQGAP3 mRNA expression. In contrast, the IQGAP2 transcript levels were reduced across different cancers viz. lung, breast, gastric, liver, kidney and colorectal cancer. IQGAP2 expression correlated positively with survivability, on the contrary, IQGAP3 expression levels correlated inversely with survivability, in most of the cancers. Collectively, enhanced IQGAP3 and reduced IQGAP2 levels were frequently observed in multiple cancers with the former predicting poor survivability and the later opposite. Methylation pattern was significantly altered in most of the cancer types. We found copy no. variation and mutations in specific cancers, for IQGAP2 and IQGAP3. Our in-vivo (IHC) data confirmed the in-silico findings completely. Hence, IQGAP2 and IQGAP3 have potential to be used as prognostic markers or therapeutic targets in specific cancers.

Dataset Information

Reduced FBXW7 expression in pancreatic cancer correlates with poor prognosis and chemotherapeutic resistance via accumulation of MCL1.

Publications

Reduced FBXW7 expression in pancreatic cancer correlates with poor prognosis and chemotherapeutic resistance via accumulation of MCL1.

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