Hypoxia Inducible Factor-1alpha (HIF-1A) plays different roles in Gallbladder Cancer and Normal Gallbladder Tissues

Abstract Purpose: Inositol polyphosphate 4-phosphatase type II (INPP4B) is a negative regulator of PI3K-Akt signaling pathway and plays a contradictory role in different types of cancers. However, its biological role in human gallbladder cancer (GBC) remain unclear. Here we aimed to investigate the expression, clinical significance and biological function of INPP4B in GBC clinical dates and GBC cell lines. Methods: The INPP4B protein expression levels in gallbladder cancer tissues and normal gallbladder tissues were detected by immunohistochemistry, and the clinical significance of INPP4B was analyzed. Knockdown and overexpression of INPP4B on GBC-SD and SGC-996 cells were used to identify INPP4B function in vitro, using cell proliferation assay, clonogenic assay, apoptosis detection, cratch wound-healing assay and transwell assay.Results: INPP4B was up-regulated in human GBC tissues compared with normal gallbladder tissues, and was related to histopathological differentiation. Here, we observed that INPP4B was highly expressed in high-moderate differentiated compared to low-undifferentiated. Additionally, we found that INPP4B expression was not associated with overall survival in GBC patients and was not an independent prognostic factor. Furthermore, when we stratified the relationship between INPP4B expression and prognosis of GBC from histopathological differentiation, we found that INPP4B played a contradictory role in GBC progression at different degrees of differentiation. In addition, INPP4B knockdown inhibited tumorigenicity in vitro, and INPP4B overexpression induced tumorigenicity in vitro, which may play a role as an oncoprotein.Conclusions: These findings implicated that INPP4B may play a dual role in the prognosis of GBC with different degrees of differentiation, and might act as an oncogene in gallbladder cancer cells.

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Expression and heterodimerization of Type A and B Cholecystokinin Receptors in Gallbladder cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e15655 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e15655-e15655

Author(s):

Abhijit Chandra ◽

Jaya Nigam ◽

Madhumati Goel ◽

Devendra Parmar ◽

Leena Khare Satyam

Keyword(s):

Western Blot ◽

Gallbladder Cancer ◽

Tumor Biology ◽

Type A ◽

Late Presentation ◽

Tissue Samples ◽

Northern India ◽

Normal Gallbladder

e15655 Background: Gallbladder cancer is the most common malignancy of the biliary tract and endemic in Northern India. The prognosis of gallbladder cancer remains dismal despite any treatment because of late presentation and aggressive tumor biology. Cholecystokinin (CCK) is present in abundance in gallbladder tissue and mediates function through two structurally related receptors, the type A (CCKAR) and B (CCKBR) receptors. Previously, heterodimerization of CCKAR and CCKBR receptor has been demonstrated in vitro, and was shown to bind natural agonists normally but exhibited agonist stimulated cellular signaling, promoting cell growth. In this study we examined the expression level of CCKAR and CCKBR in resected gallbladder tissue samples and also attempted to determine the dimerization status of CCKAR and CCKBR receptors in gallbladder cancer comparing them to cholelithiasis and normal gallbladder tissue. Methods: Tissue samples from resected normal gallbladder (n = 10), cholelithiasis (n = 25) and gallbladder cancer (n = 25)) were evaluated for the expression of CCKAR and CCKBR by immunohistochemistry. Determination of CCKAR and CCKBR expression was also done by western blot in representative samples from each of these tissue types while their dimerization status was evaluated by immunoprecipitation. Results: By Immunohistochemistry technique, positive CCKAR expression was observed in 80% gallbladder cancer, 84% cholelithiasis, 90% normal gallbladder, P = 0.76. However significantly higher expression of CCKBR was noted in gallbladder cancer (60%) as compared to cholelithiasis (25%) and normal gallbladder (20%), P = 0.013. We also observed progressively increasing level of expression of CCKAR and CCKBR in gallbladder cancer as compared to cholelithiasis and normal gallbladder by western blot. In addition, we also observed a higher level of heterodimer formation in gallbladder cancer compared to cholelithiasis and normal gallbladder using immunoprecipitation technique. Conclusions: Our results provide the first evidence of increasing trend of heterodimerization of CCKAR and CCKBR in gallbladder cancer which has potential clinical and therapeutic significance.

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Expression and functional characterization of INPP4B in gallbladder cancer patients and gallbladder cancer cells

BMC Cancer ◽

10.1186/s12885-021-08143-6 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Youliang Wu ◽

Delong Meng ◽

Xin Xu ◽

Junjun Bao ◽

Yexiang You ◽

...

Keyword(s):

Gallbladder Cancer ◽

Cancer Cells ◽

Clinical Significance ◽

Functional Characterization ◽

Negative Regulator ◽

Migration And Invasion ◽

Human Gallbladder ◽

Normal Gallbladder ◽

Degree Of Differentiation

Abstract Background Inositol polyphosphate 4-phosphatase type II (INPP4B) is a negative regulator of the PI3K-Akt signalling pathway and plays a contradictory role in different types of cancers. However, the its biological role played by INPP4B in human gallbladder cancer (GBC) has not been elucidated. In this study, we investigated the expression, clinical significance and biological function of INPP4B in GBC patients and cell lines. Methods The INPP4B protein expression levels in gallbladder cancer tissues and normal gallbladder tissues were detected by immunohistochemistry, and the clinical significance of INPP4B was analysed. Knockdown and overexpression of INPP4B in GBC-SD and SGC-996 cells followed by cell proliferation, clonogenic, apoptosis detection, scratch wound-healing and transwell assays were used to identify INPP4B function in vitro. Results INPP4B was up-regulated in human GBC tissues compared with normal gallbladder tissues and was related to histopathological differentiation (p = 0.026). Here, we observed that INPP4B was highly expressed in high-moderately differentiated tumours compared with low-undifferentiated tumours (p = 0.022). Additionally, we found that INPP4B expression was not associated with overall survival of GBC patients (p = 0.071) and was not an independent prognostic factor. Furthermore, when we stratified the relationship between INPP4B expression and the prognosis of GBC based on histopathological differentiation, we found that INPP4B played a contradictory role in GBC progression depending on the degree of differentiation. In addition, INPP4B knockdown inhibited the proliferation, colony formation, migration and invasion in GBC cells, while INPP4B overexpression had the opposite effects in vitro, which indicates its role as an oncoprotein. Conclusions These findings suggested that INPP4B may play a dual role in the prognosis of GBC depending on the degree of differentiation and that INPP4B might act as an oncogene in gallbladder cancer cells.

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Oridonin inhibits hypoxia-induced epithelial–mesenchymal transition and cell migration by the hypoxia-inducible factor-1α/matrix metallopeptidase-9 signal pathway in gallbladder cancer

Anti-Cancer Drugs ◽

10.1097/cad.0000000000000797 ◽

2019 ◽

Vol 30 (9) ◽

pp. 925-932 ◽

Cited By ~ 1

Author(s):

Kunlun Chen ◽

Jianwen Ye ◽

Lei Qi ◽

Yuan Liao ◽

Renfeng Li ◽

...

Keyword(s):

Cell Migration ◽

Gallbladder Cancer ◽

Epithelial Mesenchymal Transition ◽

Hypoxia Inducible Factor ◽

Signal Pathway ◽

Mesenchymal Transition ◽

Hypoxia Inducible Factor 1Α ◽

Matrix Metallopeptidase ◽

Matrix Metallopeptidase 9

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Vascular adaptations to hypoxia: molecular and cellular mechanisms regulating vascular tone

Essays in Biochemistry ◽

10.1042/bse0430105 ◽

2007 ◽

Vol 43 ◽

pp. 105-120 ◽

Cited By ~ 8

Author(s):

Michael L. Paffett ◽

Benjimen R. Walker

Keyword(s):

Vascular Tone ◽

Cellular Proliferation ◽

Hypoxic Pulmonary Vasoconstriction ◽

Hypoxia Inducible Factor ◽

Systemic Circulation ◽

Cellular Mechanisms ◽

Hypoxia Inducible Factor 1 ◽

Pulmonary Vasoconstriction ◽

Adaptive Mechanisms ◽

Adaptive Processes

Several molecular and cellular adaptive mechanisms to hypoxia exist within the vasculature. Many of these processes involve oxygen sensing which is transduced into mediators of vasoconstriction in the pulmonary circulation and vasodilation in the systemic circulation. A variety of oxygen-responsive pathways, such as HIF (hypoxia-inducible factor)-1 and HOs (haem oxygenases), contribute to the overall adaptive process during hypoxia and are currently an area of intense research. Generation of ROS (reactive oxygen species) may also differentially regulate vascular tone in these circulations. Potential candidates underlying the divergent responses between the systemic and pulmonary circulations may include Nox (NADPH oxidase)-derived ROS and mitochondrial-derived ROS. In addition to alterations in ROS production governing vascular tone in the hypoxic setting, other vascular adaptations are likely to be involved. HPV (hypoxic pulmonary vasoconstriction) and CH (chronic hypoxia)-induced alterations in cellular proliferation, ionic conductances and changes in the contractile apparatus sensitivity to calcium, all occur as adaptive processes within the vasculature.

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