Pathobiological implications of MUC4 in non-small-cell lung cancer

Prabin Dhangada Majhi, Imayavaramban Lakshmanan, Moorthy Palanimuthu Ponnusamy, Maneesh Jain, Srustidhar Das, Sukwinder Kaur, Su Tomohiro Shimizu, William W. West, Sonny L. Johansson, Lynette M Smith, Fang Yu, Cleo E. Rolle, Poonam Sharma, George B. Carey, Surinder Kumar Batra, Apar Kishor P Ganti

Research output: Contribution to journalArticle

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Abstract

INTRODUCTION: Altered expression of MUC4 plays an oncogenic role in various cancers, including pancreatic, ovarian, and breast. This study evaluates the expression and role of MUC4 in non-small-cell lung cancer (NSCLC). METHODS: We used a paired system of MUC4-expressing (H292) and MUC4-nonexpressing (A549) NSCLC cell lines to analyze MUC4-dependent changes in growth rate, migration, and invasion using these sublines. We also evaluated the alterations of several tumor suppressor, proliferation, and metastasis markers with altered MUC4 expression. Furthermore, the association of MUC4 expression (by immunohistochemistry) in lung cancer samples with patient survival was evaluated. RESULTS: MUC4-expressing lung cancer cells demonstrated a less proliferative and metastatic phenotype. Up-regulation of p53 in MUC4-expressing lung cancer cells led to the accumulation of cells at the G2/M phase of cell cycle progression. MUC4 expression attenuated Akt activation and decreased the expression of Cyclins D1 and E, but increased the expression of p21 and p27. MUC4 expression abrogated cancer cell migration and invasion by altering N- & E-cadherin expression and FAK phosphorylation. A decrease in MUC4 expression was observed with increasing tumor stage (mean composite score: stage I, 2.4; stage II, 1.8; stage III, 1.4; and metastatic, 1.2; p = 0.0093). Maximal MUC4 expression was associated with a better overall survival (p = 0.042). CONCLUSION: MUC4 plays a tumor-suppressor role in NSCLC by altering p53 expression in NSCLC. Decrease in MUC4 expression in advanced tumor stages also seems to confirm the novel protective function of MUC4 in NSCLC.

Original languageEnglish (US)
Pages (from-to)398-407
Number of pages10
JournalJournal of Thoracic Oncology
Volume8
Issue number4
DOIs
StatePublished - Apr 2013

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Non-Small Cell Lung Carcinoma
Lung Neoplasms
Neoplasms
Cyclin E
Survival
G2 Phase
Cyclin D1
Cadherins
Pancreatic Neoplasms
Cell Division
Cell Movement
Cell Cycle
Breast
Up-Regulation
Immunohistochemistry
Phosphorylation
Neoplasm Metastasis
Phenotype
Cell Line
Growth

Keywords

  • EMT
  • Invasion
  • Lung cancer
  • MUC4
  • Motility
  • p53

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

Cite this

Pathobiological implications of MUC4 in non-small-cell lung cancer. / Majhi, Prabin Dhangada; Lakshmanan, Imayavaramban; Palanimuthu Ponnusamy, Moorthy; Jain, Maneesh; Das, Srustidhar; Kaur, Sukwinder; Shimizu, Su Tomohiro; West, William W.; Johansson, Sonny L.; Smith, Lynette M; Yu, Fang; Rolle, Cleo E.; Sharma, Poonam; Carey, George B.; Batra, Surinder Kumar; Ganti, Apar Kishor P.

In: Journal of Thoracic Oncology, Vol. 8, No. 4, 04.2013, p. 398-407.

Research output: Contribution to journalArticle

Majhi, Prabin Dhangada ; Lakshmanan, Imayavaramban ; Palanimuthu Ponnusamy, Moorthy ; Jain, Maneesh ; Das, Srustidhar ; Kaur, Sukwinder ; Shimizu, Su Tomohiro ; West, William W. ; Johansson, Sonny L. ; Smith, Lynette M ; Yu, Fang ; Rolle, Cleo E. ; Sharma, Poonam ; Carey, George B. ; Batra, Surinder Kumar ; Ganti, Apar Kishor P. / Pathobiological implications of MUC4 in non-small-cell lung cancer. In: Journal of Thoracic Oncology. 2013 ; Vol. 8, No. 4. pp. 398-407.
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AU - Lakshmanan, Imayavaramban

AU - Palanimuthu Ponnusamy, Moorthy

AU - Jain, Maneesh

AU - Das, Srustidhar

AU - Kaur, Sukwinder

AU - Shimizu, Su Tomohiro

AU - West, William W.

AU - Johansson, Sonny L.

AU - Smith, Lynette M

AU - Yu, Fang

AU - Rolle, Cleo E.

AU - Sharma, Poonam

AU - Carey, George B.

AU - Batra, Surinder Kumar

AU - Ganti, Apar Kishor P

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N2 - INTRODUCTION: Altered expression of MUC4 plays an oncogenic role in various cancers, including pancreatic, ovarian, and breast. This study evaluates the expression and role of MUC4 in non-small-cell lung cancer (NSCLC). METHODS: We used a paired system of MUC4-expressing (H292) and MUC4-nonexpressing (A549) NSCLC cell lines to analyze MUC4-dependent changes in growth rate, migration, and invasion using these sublines. We also evaluated the alterations of several tumor suppressor, proliferation, and metastasis markers with altered MUC4 expression. Furthermore, the association of MUC4 expression (by immunohistochemistry) in lung cancer samples with patient survival was evaluated. RESULTS: MUC4-expressing lung cancer cells demonstrated a less proliferative and metastatic phenotype. Up-regulation of p53 in MUC4-expressing lung cancer cells led to the accumulation of cells at the G2/M phase of cell cycle progression. MUC4 expression attenuated Akt activation and decreased the expression of Cyclins D1 and E, but increased the expression of p21 and p27. MUC4 expression abrogated cancer cell migration and invasion by altering N- & E-cadherin expression and FAK phosphorylation. A decrease in MUC4 expression was observed with increasing tumor stage (mean composite score: stage I, 2.4; stage II, 1.8; stage III, 1.4; and metastatic, 1.2; p = 0.0093). Maximal MUC4 expression was associated with a better overall survival (p = 0.042). CONCLUSION: MUC4 plays a tumor-suppressor role in NSCLC by altering p53 expression in NSCLC. Decrease in MUC4 expression in advanced tumor stages also seems to confirm the novel protective function of MUC4 in NSCLC.

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