GOLM1 Modulates EGFR/RTK Cell-Surface Recycling to Drive Hepatocellular Carcinoma Metastasis

doi:10.1016/j.ccell.2016.07.017

. 2016 Sep 12;30(3):444-458.

doi: 10.1016/j.ccell.2016.07.017. Epub 2016 Aug 25.

GOLM1 Modulates EGFR/RTK Cell-Surface Recycling to Drive Hepatocellular Carcinoma Metastasis

Qing-Hai Ye¹, Wen-Wei Zhu², Ju-Bo Zhang³, Yi Qin⁴, Ming Lu⁵, Guo-Ling Lin¹, Lei Guo¹, Bo Zhang¹, Zhen-Hai Lin¹, Stephanie Roessler⁶, Marshonna Forgues⁷, Hu-Liang Jia⁵, Lu Lu⁵, Xiao-Fei Zhang⁵, Bao-Feng Lian⁸, Lu Xie⁸, Qiong-Zhu Dong⁹, Zhao-You Tang², Xin Wei Wang¹⁰, Lun-Xiu Qin¹¹

Affiliations

¹ Liver Cancer Institute, Fudan University, Shanghai 200032, China.
² Liver Cancer Institute, Fudan University, Shanghai 200032, China; Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai 200040, China.
³ Liver Cancer Institute, Fudan University, Shanghai 200032, China; Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China.
⁴ Institutes of Biomedical Science, Fudan University, Shanghai 200032, China; Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
⁵ Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai 200040, China.
⁶ Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA; Institute of Pathology, University Hospital Heidelberg 69120 Heidelberg, Germany.
⁷ Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
⁸ Shanghai Center for Bioinformatics Technology, Shanghai 201203, China.
⁹ Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai 200040, China; Institutes of Biomedical Science, Fudan University, Shanghai 200032, China.
¹⁰ Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA. Electronic address: xw3u@nih.gov.
¹¹ Liver Cancer Institute, Fudan University, Shanghai 200032, China; Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai 200040, China; Institutes of Biomedical Science, Fudan University, Shanghai 200032, China. Electronic address: qinlx@fudan.edu.cn.

PMID: 27569582
PMCID: PMC5021625
DOI: 10.1016/j.ccell.2016.07.017

GOLM1 Modulates EGFR/RTK Cell-Surface Recycling to Drive Hepatocellular Carcinoma Metastasis

Qing-Hai Ye et al. Cancer Cell. 2016.

. 2016 Sep 12;30(3):444-458.

doi: 10.1016/j.ccell.2016.07.017. Epub 2016 Aug 25.

Authors

Affiliations

¹ Liver Cancer Institute, Fudan University, Shanghai 200032, China.
² Liver Cancer Institute, Fudan University, Shanghai 200032, China; Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai 200040, China.
³ Liver Cancer Institute, Fudan University, Shanghai 200032, China; Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China.
⁴ Institutes of Biomedical Science, Fudan University, Shanghai 200032, China; Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
⁵ Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai 200040, China.
⁶ Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA; Institute of Pathology, University Hospital Heidelberg 69120 Heidelberg, Germany.
⁷ Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
⁸ Shanghai Center for Bioinformatics Technology, Shanghai 201203, China.
⁹ Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai 200040, China; Institutes of Biomedical Science, Fudan University, Shanghai 200032, China.
¹⁰ Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA. Electronic address: xw3u@nih.gov.
¹¹ Liver Cancer Institute, Fudan University, Shanghai 200032, China; Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai 200040, China; Institutes of Biomedical Science, Fudan University, Shanghai 200032, China. Electronic address: qinlx@fudan.edu.cn.

PMID: 27569582
PMCID: PMC5021625
DOI: 10.1016/j.ccell.2016.07.017

Abstract

The mechanism of cancer metastasis remains poorly understood. Using gene profiling of hepatocellular carcinoma (HCC) tissues, we have identified GOLM1 as a leading gene relating to HCC metastasis. GOLM1 expression is correlated with early recurrence, metastasis, and poor survival of HCC patients. Both gain- and loss-of-function studies determine that GOLM1 acts as a key oncogene by promoting HCC growth and metastasis. It selectively interacts with epidermal growth factor receptor (EGFR) and serves as a specific cargo adaptor to assist EGFR/RTK anchoring on the trans-Golgi network (TGN) and recycling back to the plasma membrane, leading to prolonged activation of the downstream kinases. These findings reveal the functional role of GOLM1, a Golgi-related protein, in EGFR/RTK recycling and metastatic progression of HCC.

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Conflict of interest statement

The author(s) indicated no potential conflicts of interest.

Figures

**Figure 1. Up-regulation of GOLM1 Correlates with Distant Metastasis and Poor Prognosis of Human HCCs**
**(A)** Hierarchical clustering using complete linkage of the gene expression profiles among HCCs with extrahepatic metastasis (EHMH), metastasis-free HCCs (MFH) and normal liver tissues (NLT) based on laser capture tissue micro-dissection, after two-cycle RNA amplification. **(B)** The lead gene, *GOLM1*, was significantly upregulated in EHMH compared with MFH and NLT. **(C–E)** GOLM1 expression correlates with EHMH. **(C)** qRT-PCR analysis of *GOLM1* mRNA in the NLT (n = 11), cirrhotic liver tissue (CLT, n = 20), MFH (n = 20), and EHMH (n = 40). Error bars indicate mean ± SD. **(D)** Representative images of immunohistochemical (IHC) staining of GOLM1 in NLT, CLT, MFH, and EHMH specimens. Scale bars, 50 μm. **(E)** Quantification of GOLM1 expression according to IHC scores (see below) in NLT (n = 40), CLT (n = 21), MFH (n = 40), and EHMH (n = 40), respectively. Significance was determined using the χ² test. **(F)** Difference of GOLM1 levels between 15 pairs HCCs with early recurrence (ER) or recurrence-free (RF) status after curative resection detected by Western-blot. The expression of GOLM1 was normalized against GAPDH, according to the intensity of each lane with the use of a computerized image system (Quantity one-4.6.2, Bio-Rad Laboratories, CA). The intensity higher than the median was defined as high expression. **(G)** Scores indicate GOLM1 levels in representative tumor tissues. The scores were calculated by intensity and percentage of stained cells as described in the Supplements. **(H, I)** The patients with high GOLM1 expression (Score 2–3) have poorer overall survival and higher probability of recurrence compared with low GOLM1 expression (Score 0–1) patients in both testing cohort 1 **(H)** and validation cohort 2 **(I)**. Scores of two patients were unexpectedly detached from TMA without sufficient tissue in Cohort 2. See also Figures S1 and Tables S1–S4.

**Figure 2. Roles of GOLM1 in Promoting HCC Growth and Metastasis**
**(A)** Confirmation of GOLM1 knockdown (KD, shGOLM1) and reexpression (shRES), and overexpression (GOLM1^FLAG) in HCC cell lines. **(B–D)** The effects of GOLM1 gain- or loss-of-function on in vitro proliferation **(B)**, migration **(C)**, and invasion **(D)** of HCC cells. KD of GOLM1 resulted in significant inhibited proliferation (B, a–b), migration (C, a), and invasion (D, a) of MHCC-97H and Huh-7 cells, which is counteracted by shRES in MHCC-97H and Huh-7 cells. GOLM1 up-regulation significantly increased cell proliferation (B, c–d), migration (C, b), and invasion (D, b) abilities. Error bars indicate mean ± SEM. *p < 0.05; #p > 0.05. **(E)** The dynamic change of tumor volume between MHCC-97H^shNT and MHCC-97H^shGOLM1 subcutaneous model are shown. Error bars indicate mean ± SEM. **(F–H)** Down-regulation of GOLM1 significantly suppressed spontaneous lung metastasis in subcutaneous **(F)** and xenograft **(G,H)** HCCs nude mice models. (G) Representative H&E staining images in lung tissues of three xenograft groups. Scale bar = 100 μm. Arrowheads indicate lung metastatic nodules, and the areas labeled with Δ in the upper panel are shown in the lower panel with higher magnification. WT, wild type. Significance was determined by the χ² test. For (F) and (H), Error bars indicate mean ± SD. **(I)** KD of GOLM1 prolonged overall survival of xenograft mice models bearing HCCs. See also Figures S2.

**Figure 3. GOLM1 Interacts with EGFR/RTK and Facilitates Its Downstream Signaling**
**(A)** Mass spectrometry (MS) analysis of GOLM1-associated proteins. Total cell lysates extract from GOLM1^FLAG stably expressed cells were subjected to affinity purification. The purified protein complex was resolved on SDS-PAGE and sliver stained then the bands were retrieved and analyzed by MS. **(B)** Analyses of identified GOLM1-interactors. A diagram depicts GOLM-interactors as detected by MS. The network was built based on the interaction network of EGFR associated vesicle-mediated traffic processes in the HIPPIE database overlaid with MS data (detailed in supplemental experimental procedures). **(C,D)** Interaction between exogenous GOLM1 and EGFR. Total cell lysates from GOLM1^FLAG stably expressing Hep3B (C) and PLC (D) cells were prepared, then immunoprecipitation (IP) and immunoblotting (IB) were performed with anti-FLAG or anti-EGFR antibodies. **(E)** Interaction of endogenous GOLM1 with EGFR determined by Co-IP analyses in MHCC-97H cell. **(F)** Down-regulation of GOLM1 significantly attenuates EGF-induced downstream signaling. MHCC-97H cells stably expressed shGOLM1, shNT or shRES when treated with EGF. IB examination of both phosphorylated AKT (Ser 473) and S6K (Thr389) are shown and quantified in the right panel. *p < 0.05; #p > 0.05. See also Figures S3 and Table S5.

**Figure 4. GOLM1 Recruits to EGFR/RTK upon Ligand Dynamically Binding**
**(A)** Effects of EGF stimulation on intracellular distribution of GOLM1. Left panel: Co-localizations of GOLM1 (green) with TGN46 (TGN, red) were detected in MHCC-97H cells in the normal state. Right panel: Under EGF stimulation (100 ng/ml), GOLM1 disperses from TGN to cytoplasm to form endosome-like structures (arrowheads). DNA was labeled with DAPI (blue). **(B)** The co-localization of dispersed GOLM1 (green) and EGFR (red) in MHCC-97H (a) and PLC-GOLM1^FLAG (b) cells after EGF stimulation. Arrowheads indicate the co-localization of GOLM1 with EGFR endosome-like structures. **(C)** The real-time co-localization of GOLM1 (red) with EGFR (green) in PLC cells treated with EGF.at indicated times Arrowheads point to the co-localization of EGFR and GOLM1, respectively. See details in the supplementary video S1 **(D,E)**, GOLM1 dynamically interacts with EGFR in PLC-GOLM1^FLAG cells treated with EGF (100 ng/ml) for the indicated times when subjected to Co-IP (D) and confocal microscopic (E) analysis. Total cell lysates were subjected to IP with EGFR and IB antibodies as indicated (upper panel). The interaction between GOLM1 and EGFR (dark line) increases as EGF stimulation decreases, with the strongest interaction at 30 min then declines over time. The corresponding AKT phosphorylation (red line) changed with a similar pattern (lower panel). Values are presented as mean ± SEM. **(D)** The representative images of co-localization between GOLM1 (green) and EGFR (red) are shown in the left panel; the right panel shows the result of semi-quantitative analysis with a percentage of yellow pixels versus red pixels as indicated in Supplementary Fig S7 **(E)**. Right panel: values are presented as mean ± SEM from at least three experiments (n > 10 cells). *p < 0.05; **p < 0.01. **(F)** Loss of GOLM1 impairs EGFR transportation from TGN to plasma membrane (PM). MHCC-97H^shNT and MHCC-97H^shGOLM1 cells, transfected with GFP–EGFR overnight, were treated with EGF and subjected to temperature block and release assay. The upper bar of the left panel describes the experimental procedures. Western blot (left panel) and confocal microscopic images (right panel) demonstrate that EGFR (green), in MHCC-97H^shNT cells, was transported from predominantly TGN (red) to the plasma membrane (arrowheads), however, in MHCC-97H^shGOLM1 cells, EGFR was still co-localized more with TGN than on the PM. TO: total. See also Figures S4 and Movies S1–S2.

**Figure 5. GOLM1 Regulates and HCC Cell Migration through EGFR/RTK Recycling**
**(A)** GOLM1 knockdown enhances EGF-induced EGFR degradation. Western-blot detected the alterations of total EGFR degradation in MHCC-97H^shNT and MHCC-97H ^shGOLM1 cells in response to EGF stimulation in the presence of cycloheximide (upper panel). Densitometric analysis of EGFR blots from three independent experiments, are shown as mean ± SEM (lower panel). **(B)** KD of GOLM1 weakens EGFR recycling. Different treatment MHCC-97H and Huh-7 cells were surface labeled on ice with Sulfo-NHS-SS-biotin, stimulated for 15 min with EGF at 37°C. The recycling of EGFR was determined as described in the Supplementary Materials and Methods. Values are means ± SEM of 9 replicates from three independent experiments. **(C)** Co-localization analysis of EGFR with Rab11, Lamp1, and Lamp2 after EGF treatment for 15 min. Unlike MHCC-97H^shNT cells, EGFR rarely has the opportunity to co-localize with Rab11, while the lysosome was enriched (Lamp1 and Lamp2) in MHCC-97H^shGOLM1. Co-localization index are shown in the lower left corner. **(D–F)** Mapping of the binding site of GOML1 / EGFR in vivo. Diagrammatic representation of GOLM1 and its truncated forms. Based on sequence and structure analyses, region I (cytoplasmic domain), region II (transmembrane domain) and region III–V (Golgi lumen domains) are indicated **(D)**. PLC cells were transfected with the indicated constructs. Twenty-four hr after transfection, cells were harvested, lysed, and subjected to immunoprecipitation with anti-Flag (against GOLM1). Immunoblot analysis was performed with anti-FLAG or anti-EGFR antibodies **(E, F)** **(G)** Effects of GOLM1 mutation on EGFR recycling in HCC cells. The recycling of EGFR was determined in MHCC-97H and PLC cells stable expressing shNT, shGOLM1, shGOLM1-Res vectors as well as different GOLM1 mutants as indicated. Error bars indicate mean ± SEM. **(H)** Effects of GOLM1 mutation on migration abilities of HCC cells. MHCC-97H and PLC cells stable expressing shNT, shGOLM1, shGOLM1-Res vectors as well as different GOLM1 mutants as indicated. The different combinations of them were subjected to transwell migration assay. The fold differences represent the mean of triplicate experiments compared with controls. Error bars indicate mean ± SEM. *p < 0.05, #p > 0.05 as determined by a Student’s t test. See also Figures S5–S8.

**Figure 6. Rab11 Is Required for GOLM1-Mediated EGFR/RTK Recycling and Cell Migration**
**(A)** MHCC-97H cells were transfected with shRNAs _targeting endogenous Rab11 and the recycling of EGFR were determined. Values are means ± SEM of 9 replicates from three independent experiments. **(B–D)** Down-regulation of Rab11 suppressed EGFR downstream AKT activation upon EGF binding **(B)**, cell migration **(C)** and invasion **(D)** capabilities compared with non-_targeting shRNA. The fold difference represents the mean of triplicate experiments compared with control cells. Error bars indicate mean ± SEM. *p < 0.05. **(E)** The recycling of EGFR was determined in MHCC-97H and Huh-7 cells stable expressing shNT, shGOLM1, shRab11, shGOLM1-Res vector as indicated. Error bars indicate mean ± SEM. **(F)** Effects of KD of GOLM1 and Rab11 on the migration abilities of HCC cells. MHCC-97H cells stable expressing shNT, shGOLM1, shRab11, shGOLM1-Res or shRab11-Res. The different combinations of them were subjected to transwell migration assay. The fold differences represent the mean of triplicate experiments compared with controls. Error bars indicate mean ± SEM. *p < 0.05, #p > 0.05 as determined by a Student’s t test. **(G)** Immunoprecipitation of endogenous EGFR from control or GOLM1 knockdown MHCC-97H cells after treatment with EGF. The input protein levels (down panel) and those present in immunoprecipitates (up panel) were determined by western blotting. **(H)** GOLM1 interacts with Rab11. The indicated constructs (FLAG-GOLM1 and HA-Rab11) were transiently expressed in 293T cells and the whole cell lysates were immunoprecipitated (IP) with anti-FLAG antibody. **(I)** In vitro interaction between GOLM1 and Rab11. Whole cell lysates from PLC cells stably expressing GOLM1^FLAG were prepared, and IP and IB were performed with antibodies as indicated.

**Figure 7. Interfering GOLM1 Exocrinosity or Golgi Anchoring Reduced EGFR Recycling in Response to EGF Stimulation, Resulting in Compromised HCC Cell Migration**
**(A)** Schematic diagram depicts GOLM1 mutants used in this study. **(B)** Western-blot results demonstrate that the secreted GOLM1^FLAG density in culture media (GOLM1^CCM) significantly decreased when signal peptides were mutated from RVRR to RVAA (RVAA-PLC) **(C)** Confocal microscope images demonstrate the effects of the transmembrane domain deletion GOLM1 (GOLM1^TMD) on its intracellular distribution and interaction with EGFR. The GOLM1^FLAG in GOLM1^FLAG-PLC is mainly distributed on TGN (a), and co-localized with EGFR when stimulated with EGF (b). While GOLM1^TMD in GOLM1^TMD-PLC scattered in the cytoplasm, there was rare co-localization with TGN (c) or EGFR (d) in response to EGF stimulation. **(D, E)** IP and IB were used to evaluate the effects of GOLM1^TMD on its interaction with EGFR to activate down-stream signaling upon EGF stimulation. **(D)** Compared with GOLM1^FLAG-PLC, the interaction of EGFR with GOLM1^TMD in GOLM1^TMD-PLC was significantly reduced over time after EGF stimulation, accompanied by decreased phosphorylation of AKT and S6K. **(E)** The relative amounts of phosphorylated AKT and S6K compared with their total levels determined by densitometric analysis. Results are expressed as mean ± SEM. **(F)** The reduced EGFR recycling in RVAA-GOLM1 and GOLM1^TMD treated PLC cells was detected as described in the Experimental Procedures. **(G,H)** The changes of AKT and S6K phosphorylation, and migration abilities were detected by Western blot **(G)**, and transwell assay **(H)** in MHCC-97H transfect with indicated vectors, respectively. With the exception of GOLM^shRES, the re-introduction of GOLM1-RVAA or GOLM1^TMD mutants did not rescue the decreased levels of phosphorylated AKT and S6K, as well as EGF chemoattractant migration of MHCC-97H^shGOLM1 cells. Values are presented as mean ± SEM from at least three experiments, *p < 0.05, #p > 0.05.

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Powering Tumor Metastasis with Recycled Fuel.
Hung MC, Yang R, Sun Y. Hung MC, et al. Cancer Cell. 2016 Sep 12;30(3):374-375. doi: 10.1016/j.ccell.2016.08.014. Cancer Cell. 2016. PMID: 27622330

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References

1. Abella JV, Park M. Breakdown of endocytosis in the oncogenic activation of receptor tyrosine kinases. Am J Physiol Endocrinol Metab. 2009;296:E973–E984. - PubMed
1. Buschman MD, Rahajeng J, Field SJ. GOLPH3 links the Golgi, DNA damage, and cancer. Cancer Res. 2015;75:624–627. - PMC - PubMed
1. Casaletto JB, McClatchey AI. Spatial regulation of receptor tyrosine kinases in development and cancer. Nat Rev Cancer. 2012;12:387–400. - PMC - PubMed
1. Caswell PT, Chan M, Lindsay AJ, McCaffrey MW, Boettiger D, Norman JC. Rab-coupling protein coordinates recycling of alpha5beta1 integrin and EGFR1 to promote cell migration in 3D microenvironments. J Cell Biol. 2008;183:143–155. - PMC - PubMed
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[1] Abella JV, Park M. Breakdown of endocytosis in the oncogenic activation of receptor tyrosine kinases. Am J Physiol Endocrinol Metab. 2009;296:E973–E984. - PubMed

[2] Abella JV, Park M. Breakdown of endocytosis in the oncogenic activation of receptor tyrosine kinases. Am J Physiol Endocrinol Metab. 2009;296:E973–E984. - PubMed

[3] Buschman MD, Rahajeng J, Field SJ. GOLPH3 links the Golgi, DNA damage, and cancer. Cancer Res. 2015;75:624–627. - PMC - PubMed

[4] Buschman MD, Rahajeng J, Field SJ. GOLPH3 links the Golgi, DNA damage, and cancer. Cancer Res. 2015;75:624–627. - PMC - PubMed

[5] Casaletto JB, McClatchey AI. Spatial regulation of receptor tyrosine kinases in development and cancer. Nat Rev Cancer. 2012;12:387–400. - PMC - PubMed

[6] Casaletto JB, McClatchey AI. Spatial regulation of receptor tyrosine kinases in development and cancer. Nat Rev Cancer. 2012;12:387–400. - PMC - PubMed

[7] Caswell PT, Chan M, Lindsay AJ, McCaffrey MW, Boettiger D, Norman JC. Rab-coupling protein coordinates recycling of alpha5beta1 integrin and EGFR1 to promote cell migration in 3D microenvironments. J Cell Biol. 2008;183:143–155. - PMC - PubMed

[8] Caswell PT, Chan M, Lindsay AJ, McCaffrey MW, Boettiger D, Norman JC. Rab-coupling protein coordinates recycling of alpha5beta1 integrin and EGFR1 to promote cell migration in 3D microenvironments. J Cell Biol. 2008;183:143–155. - PMC - PubMed

[9] Ceresa BP. Regulation of EGFR endocytic trafficking by rab proteins. Histol Histopathol. 2006;21:987–993. - PubMed

[10] Ceresa BP. Regulation of EGFR endocytic trafficking by rab proteins. Histol Histopathol. 2006;21:987–993. - PubMed

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GOLM1 Modulates EGFR/RTK Cell-Surface Recycling to Drive Hepatocellular Carcinoma Metastasis

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GOLM1 Modulates EGFR/RTK Cell-Surface Recycling to Drive Hepatocellular Carcinoma Metastasis

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