MUC16 contributes to the metastasis of pancreatic ductal adenocarcinoma through focal adhesion mediated signaling mechanism

Sakthivel Muniyan, Dhanya Haridas, Seema Chugh, Satyanarayana Rachagani, Imayavaramban Lakshmanan, Suprit Gupta, Parthasarathy Seshacharyulu, Lynette M Smith, Moorthy Palanimuthu Ponnusamy, Surinder Kumar Batra

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

MUC16, a heavily glycosylated type-I transmembrane mucin is overexpressed in several cancers including pancreatic ductal adenocarcinoma (PDAC). Previously, we have shown that MUC16 is significantly overexpressed in human PDAC tissues. However, the functional consequences and its role in PDAC is poorly understood. Here, we show that MUC16 knockdown decreases PDAC cell proliferation, colony formation and migration in vitro. Also, MUC16 knockdown decreases the tumor formation and metastasis in orthotopic xenograft mouse model. Mechanistically, immunoprecipitation and immunofluorescence analyses confirms MUC16 interaction with galectin-3 and mesothelin in PDAC cells. Adhesion assay displayed decreased cell attachment of MUC16 knockdown cells with recombinant galectin-1 and galectin-3 protein. Further, CRISPR/Cas9-mediated MUC16 knockout cells show decreased tumor-associated carbohydrate antigens (T and Tn) in PDAC cells. Importantly, carbohydrate antigens were decreased in the region that corresponds to MUC16 and suggests for the decreased MUC16-galectin interactions. Co-immunoprecipitation also revealed a novel interaction between MUC16 and FAK in PDAC cells. Interestingly, we observed decreased expression of mesenchymal and increased expression of epithelial markers in MUC16-silenced cells. Additionally, MUC16 loss showed a decreased FAK-mediated Akt and ERK/MAPK activation. Altogether, these findings suggest that MUC16-focal adhesion signaling may play a critical role in facilitating PDAC growth and metastasis.

Original languageEnglish (US)
Pages (from-to)110-124
Number of pages15
JournalGenes and Cancer
Volume7
Issue number3-4
StatePublished - Mar 2016

Fingerprint

Focal Adhesions
Adenocarcinoma
Neoplasm Metastasis
Galectin 3
Immunoprecipitation
Clustered Regularly Interspaced Short Palindromic Repeats
Tumor-Associated Carbohydrate Antigens
Galectin 1
Galectins
Mucins
Pancreatic Neoplasms
Heterografts
Fluorescent Antibody Technique
Carbohydrates
Cell Proliferation
Antigens
Growth

Keywords

  • FAK and CRISPR/Cas9
  • MUC16
  • Metastasis
  • Pancreatic cancer

ASJC Scopus subject areas

  • Genetics
  • Cancer Research

Cite this

MUC16 contributes to the metastasis of pancreatic ductal adenocarcinoma through focal adhesion mediated signaling mechanism. / Muniyan, Sakthivel; Haridas, Dhanya; Chugh, Seema; Rachagani, Satyanarayana; Lakshmanan, Imayavaramban; Gupta, Suprit; Seshacharyulu, Parthasarathy; Smith, Lynette M; Palanimuthu Ponnusamy, Moorthy; Batra, Surinder Kumar.

In: Genes and Cancer, Vol. 7, No. 3-4, 03.2016, p. 110-124.

Research output: Contribution to journalArticle

Muniyan, Sakthivel ; Haridas, Dhanya ; Chugh, Seema ; Rachagani, Satyanarayana ; Lakshmanan, Imayavaramban ; Gupta, Suprit ; Seshacharyulu, Parthasarathy ; Smith, Lynette M ; Palanimuthu Ponnusamy, Moorthy ; Batra, Surinder Kumar. / MUC16 contributes to the metastasis of pancreatic ductal adenocarcinoma through focal adhesion mediated signaling mechanism. In: Genes and Cancer. 2016 ; Vol. 7, No. 3-4. pp. 110-124.
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